PDE1 inhibitory compounds and methods

ABSTRACT

Optionally substituted (1- or 3-oxy)-4,5,7,8-tetrahydro-(optionally 4-oxo, 4-thioxo or 4-imino)-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or (1- or 3-oxy)-4,5,7,8,9-pentahydro-(optionally 4-oxo, 4-thioxo or 4-imino)-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine compounds, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising the same.

CROSS REFERENCE TO RELATED APPLICATION

This application is a United States Application under 35 U.S.C. 371claiming benefit of PCT Application No. PCT/US2011/038548, filed on May31, 2011, which claims priority from U.S. Provisional Application No.61/349,960, filed May 31, 2010, the contents of each of which are herebyincorporated by reference in their entirety.

TECHNICAL FIELD

The present invention relates to optionally substituted (1- or3-oxy)-4,5,7,8-tetrahydro-(optionally 4-oxo, 4-thioxo or4-imino)-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or (1- or3-oxy)-4,5,7,8,9-pentahydro-(optionally 4-oxo, 4-thioxo or4-imino)-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine, for example,compounds of Formula II (Formula II-A and II-B) as described below,processes for their production, their use as pharmaceuticals andpharmaceutical compositions comprising them. Of particular interest arenovel compounds useful as inhibitors of phosphodiesterase 1 (PDE1),e.g., in the treatment of diseases involving disorders of the dopamineD1 receptor intracellular pathway, such as Parkinson's disease,depression, narcolepsy, damage to cognitive function, e.g., inschizophrenia, or disorders that may be ameliorated through enhancedprogesterone-signaling pathway, e.g., female sexual dysfunction as wellas other disease or conditions characterized by low levels of cAMPand/or cGMP in cells expressing PDE1 and those characterized by reduceddopamine D1 receptor signaling activities.

BACKGROUND OF THE INVENTION

Eleven families of phosphodiesterases (PDEs) have been identified butonly PDEs in Family I, the Ca²⁺-calmodulin-dependent phosphodiesterases(CaM-PDEs), have been shown to mediate both the calcium and cyclicnucleotide (e.g. cAMP and cGMP) signaling pathways. The three knownCaM-PDE genes, PDE1A, PDE1B, and PDE1C, are all expressed in centralnervous system tissue. PDE1A is expressed throughout the brain withhigher levels of expression in the CA1 to CA3 layers of the hippocampusand cerebellum and at a low level in the striatum. PDE1A is alsoexpressed in the lung and heart. PDE1B is predominately expressed in thestriatum, dentate gyms, olfactory tract and cerebellum, and itsexpression correlates with brain regions having high levels ofdopaminergic innervation. Although PDE1B is primarily expressed in thecentral nervous system, it may be detected in the heart. PDE1C isprimarily expressed in olfactory epithelium, cerebellar granule cells,and striatum. PDE1C is also expressed in the heart and vascular smoothmuscle.

Cyclic nucleotide phosphodiesterases decrease intracellular cAMP andcGMP signaling by hydrolyzing these cyclic nucleotides to theirrespective inactive 5′-monophosphates (5′AMP and 5′GMP). CaM-PDEs play acritical role in mediating signal transduction in brain cells,particularly within an area of the brain known as the basal ganglia orstriatum. For example, NMDA-type glutamate receptor activation and/ordopamine D2 receptor activation result in increased intracellularcalcium concentrations, leading to activation of effectors such ascalmodulin-dependent kinase II (CaMKII) and calcineurin and toactivation of CaM-PDEs, resulting in reduced cAMP and cGMP. Dopamine D1receptor activation, on the other hand, leads to activation ofnucleotide cyclases, resulting in increased cAMP and cGMP. These cyclicnucleotides in turn activate protein kinase A (PKA; cAMP-dependentprotein kinase) and/or protein kinase G (PKG; cGMP-dependent proteinkinase) that phosphorylate downstream signal transduction pathwayelements such as DARPP-32 (dopamine and cAMP-regulated phosphoprotein)and cAMP responsive element binding protein (CREB). PhosphorylatedDARPP-32 in turn inhibits the activity of protein phosphates-1 (PP-1),thereby increasing the state of phosphorylation of substrate proteinssuch as progesterone receptor (PR), leading to induction of physiologicresponses. Studies in rodents have suggested that inducing cAMP and cGMPsynthesis through activation of dopamine D1 or progesterone receptorenhances progesterone signaling associated with various physiologicalresponses, including the lordosis response associated with receptivityto mating in some rodents. See Mani, et al., Science (2000) 287: 1053,the contents of which are incorporated herein by reference.

CaM-PDEs can therefore affect dopamine-regulated and other intracellularsignaling pathways in the basal ganglia (striatum), including but notlimited to nitric oxide, noradrenergic, neurotensin, CCK, VIP,serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA,acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor,natriuretic peptide (e.g., ANP, BNP, CNP), DARPP-32, and endorphinintracellular signaling pathways.

Phosphodiesterase (PDE) activity, in particular, phosphodiesterase 1(PDE1) activity, functions in brain tissue as a regulator of locomotoractivity and learning and memory. PDE1 is a therapeutic target forregulation of intracellular signaling pathways, preferably in thenervous system, including but not limited to a dopamine D1 receptor,dopamine D2 receptor, nitric oxide, noradrenergic, neurotensin, CCK,VIP, serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA,acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor,natriuretic peptide (e.g., ANP, BNP, CNP), endorphin intracellularsignaling pathway and progesterone signaling pathway. For example,inhibition of PDE1B should act to potentiate the effect of a dopamine D1agonist by protecting cGMP and cAMP from degradation, and shouldsimilarly inhibit dopamine D2 receptor signaling pathways, by inhibitingPDE1 activity. Chronic elevation in intracellular calcium levels islinked to cell death in numerous disorders, particularly inneurodegerative diseases such as Alzheimer's, Parkinson's andHuntington's Diseases and in disorders of the circulatory system leadingto stroke and myocardial infarction. PDE1 inhibitors are thereforepotentially useful in diseases characterized by reduced dopamine D1receptor signaling activity, such as Parkinson's disease, restless legsyndrome, depression, narcolepsy and cognitive impairment. PDE1inhibitors are also useful in diseases that may be alleviated by theenhancement of progesterone-signaling such as female sexual dysfunction.

There is thus a need for compounds that selectively inhibit PDE1activity, especially PDE1A and/or PDE1B activity.

SUMMARY OF THE INVENTION

The invention provides optionally substituted4,5,7,8-tetrahydro-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or4,5,7,8,9-pentahydro-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine, e.g., aCompound of Formula II, e.g., II-A or II-B:

wherein

-   -   (i) Q is C(═O), C(═S), C(═N(R₂₀)) or CH₂;    -   (ii) L is —O—;    -   (iii) R₁ is H or C₁₋₄ alkyl (e.g., methyl);    -   (iv) R₄ is H or C₁₋₆ alkyl (e.g., methyl or isopropyl) and R₂        and R₃ are, independently,        -   H        -   C₁₋₆alkyl (e.g., methyl, isopropyl) optionally substituted            with halo or hydroxy (e.g., R₂ and R₃ are both methyl, or R₂            is H and R₃ is methyl, ethyl, isopropyl or hydroxyethyl),        -   aryl,        -   heteroaryl,        -   (optionally hetero)arylalkoxy,        -   (optionally hetero)arylC₁₋₆alkyl; or        -   R₂ and R₃ together form a 3- to 6-membered ring;    -   or    -   R₂ is H and R₃ and R₄ together form a di-, tri- or        tetramethylene bridge (pref. wherein the R₃ and R₄ together have        the cis configuration, e.g., where the carbons carrying R₃ and        R₄ have the R and S configurations, respectively);    -   or    -   (v) R₅ is        -   a) -D-E-F, wherein:            -   D is C₁₋₄alkylene (e.g., methylene, ethylene or                prop-2-yn-1-ylene);            -   E is a single bond, C₂₋₄alkynylene (e.g., —C≡C—),                arylene (e.g., phenylene) or heteroarylene (e.g.,                pyridylene);            -   F is                -   H,                -   aryl (e.g., phenyl),                -   heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for                    example, pyrid-2-yl, imidazol-1-yl,                    1,2,4-triazol-1-yl),                -   halo (e.g., F, Br, Cl),                -   haloC₁₋₄alkyl (e.g., trifluoromethyl),                -   C₁₋₆ alkoxy (e.g., methoxy),                -   —C(O)—R₁₅,                -   —N(R₁₆)(R₁₇), or                -   C₃₋₇cycloalkyl optionally containing at least one                    atom selected from a group consisting of N or O                    (e.g., cyclopentyl, cyclohexyl, pyrrolidinyl (e.g.,                    pyrrolidin-3-yl or pyrrolidin-2-yl),                    tetrahydro-2H-pyran-4-yl, or morpholinyl);            -   wherein D, E and F are independently and optionally                substituted with one or more halo (e.g., F, Cl or Br),                C₁₋₄alkyl (e.g., methyl), haloC₁₋₄alkyl (e.g.,                trifluoromethyl), C₁₋₆ alkoxy (e.g., methoxy), hydroxy,                C₁₋₆-carboxy, or an additional aryl or heteroaryl (e.g.,                biphenyl or pyridylphenyl),            -   for example, F is heteroaryl, e.g., pyridyl substituted                with one or more halo (e.g., 6-fluoropyrid-2-yl,                5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,                3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl,                4,6-dichloropyrid-2-yl), haloC₁₋₆alkyl (e.g.,                5-trifluoromethylpyrid-2-yl) or C₁₋₆ alkyl (e.g.,                5-methylpyrid-2-yl), or F is aryl, e.g., phenyl,                substituted with one or more halo (e.g., 4-fluorophenyl)                or F is a C₃₋₇heterocycloalkyl (e.g., pyrrolidinyl or                piperidinyl) optionally substituted with a C₁₋₆alkyl                (e.g., 1-methylpyrrolidin-3-yl or                1-methylpyrrolidin-2-yl); or        -   b) a substituted heteroarylalkyl, e.g., substituted with            haloC₁₋₆alkyl;        -   c) attached to the nitrogen on the pyrrolo portion of            Formula II-A or II-B and is a moiety of Formula A

-   -   -   -   wherein X, Y and Z are, independently, N or C, and R₈,                R₉, R₁₁ and R₁₂ are independently H or halogen (e.g., Cl                or F), and R₁₀ is                -   halogen,                -   C₁₋₆alkyl,                -   haloC₁₋₆alkyl (e.g., trifluoromethyl)                -   C₁₋₆alkoxy (e.g. methoxy),                -   C₃₋₇cycloalkyl,                -   heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl or                    piperidinyl),                -   C₁₋₆haloalkyl (e.g., trifluoromethyl),                -   aryl (e.g., phenyl),                -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl or                    pyrid-4-yl), or thiadiazolyl (e.g.,                    1,2,3-thiadiazol-4-yl)), diazolyl (e.g.,                    imidazol-1-yl), triazolyl (e.g.,                    1,2,4-triazol-1-yl), tetrazolyl,                -   arylcarbonyl (e.g., benzoyl),                -   C₁₋₆alkylsulfonyl (e.g., methylsulfonyl),                -   heteroarylcarbonyl, or                -   C₁₋₆alkoxycarbonyl;            -   wherein the aryl, heteroaryl, cycloalkyl or                heterocycloalkyl is independently, optionally                substituted with one or more C₁₋₆alkyl (e.g., methyl),                halogen (e.g., chloro or fluoro), haloC₁₋₆alkyl (e.g.,                trifluoromethyl), hydroxy, C₁₋₆-carboxy, —SH or an                additional aryl, heteroaryl (e.g., biphenyl or                pyridylphenyl) or C₃₋₈cycloalkyl,            -   preferably R₁₀ is phenyl, pyridyl, piperidinyl or                pyrrolidinyl optionally substituted with the                substituents previously defined, e.g. optionally                substituted with halo or C₁₋₆alkyl            -   provided that when X, Y, or Z is nitrogen, R₈, R₉, or                R₁₀, respectively, is not present;

    -   (vi) R₆ is        -   C₁₋₆alkyl (e.g., isopropyl),        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or        -   arylC₁₋₆alkyl (e.g., benzyl),        -   wherein the aryl or heteroaryl is optionally substituted            with one or more group selected from halo (e.g., F, Cl),            hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl, for            example, R₆ is 3-chlorophenyl or 4-fluorophenyl;

    -   (vii) R₇ is H, C₁₋₆alkyl (e.g., methyl or ethyl), halogen (e.g.,        Cl), —N(R₁₈)(R₁₉), hydroxy or C₁₋₆alkoxy;

    -   (viii) n=0 or 1;

    -   (ix) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,        independently, H or C₁₋₆alkyl, aryl, heteroaryl, (optionally        hetero)arylC₁₋₆alkoxy, (optionally hetero)arylC₁₋₆alkyl or R₁₄        can form a bridge with R₂ or R₄;

    -   (x) R₁₅ is C₁₋₆alkyl, haloC₁₋₆alkyl, —OH or —OC₁₋₆alkyl (e.g.,        —OCH₃)

    -   (xi) R₁₆ and R₁₇ are independently H or C₁₋₆alkyl;

    -   (xii) R₁₈ and R₁₉ are independently        -   H,        -   C₁₋₆alky (e.g., methyl, ethyl, n-propyl, isobutyl),        -   C₃₋₈cycloalkyl (e.g., cyclohexyl or cyclopentyl),        -   heteroC₃₋₈cycloalkyl (e.g., pyrrolidinyl, piperidinyl,            morpholinyl),        -   aryl (e.g., phenyl) or        -   heteroaryl (e.g., pyridyl),        -   wherein said aryl and heteroaryl are optionally substituted            with one or more            -   halo (e.g., fluorophenyl, e.g., 4-fluorophenyl),            -   hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or                2-hydroxyphenyl),            -   C₁₋₆alkyl (e.g., methyl),            -   haloC₁₋₆alkyl (e.g., trifluoromethyl),            -   carboxy, or            -   an additional aryl, heteroaryl (e.g., biphenyl or                pyridylphenyl) or C₃₋₈cycloalkyl,

    -   (xiii) R₂₀ is H, C₁₋₆alkyl or C₃₋₇cycloalkyl;        in free or salt form.

The invention further provides compounds of Formula II-A or II-B asfollows:

-   -   1.1 Formula II-A or II-B, wherein Q is C(═O), C(═S), C(═N(R₂₀))        or CH₂;    -   1.2 Formula II-A or II-B or 1.1, wherein Q is C(═S);    -   1.3 Formula II-A or II-B or 1.1, wherein Q is C(═N(R₂₀));    -   1.4 Formula II-A or II-B or 1.1, wherein Q is CH₂;    -   1.5 Formula II-A or II-B or 1.1, wherein Q is C(═O);    -   1.6 Formula II-A or II-B, or any of 1.1-1.5, wherein L is —O—;    -   1.7 Formula II-A or II-B, or any of 1.1-1.6, wherein R₁ is H or        C₁₋₆ alkyl (e.g., methyl);    -   1.8 Formula 1.7, wherein R₁ is H,    -   1.9 Formula 1.7, wherein R₁ is C₁₋₆ alkyl (e.g., methyl);    -   1.10 Formula II-A or II-B, or any of 1.1-1.9, wherein R₄ is H or        C₁₋₆ alkyl (e.g., methyl, isopropyl) and R₂ and R₃ are,        independently,        -   H or C₁₋₆alkyl optionally substituted with halo or hydroxy            (e.g., R₂ and R₃ are both methyl, or R₂ is H and R₃ is            methyl, ethyl, isopropyl or hydroxyethyl),        -   aryl,        -   heteroaryl,        -   (optionally hetero)arylalkoxy, or        -   (optionally hetero)arylC₁₋₆alkyl;    -   1.11 Formula II-A or II-B, or any of 1.1-1.9, wherein R₂ is H        and R₃ and R₄ together form a di-, tri- or tetramethylene bridge        (pref. wherein the R₃ and R₄ together have the cis        configuration, e.g., where the carbons carrying R₃ and R₄ have        the R and S configurations, respectively);    -   1.12 Formula II-A or II-B or any of 1.1-1.11, wherein R₅ is        -D-E-F;    -   1.13 Formula 1.12, wherein D is C₁₋₆alkylene (e.g., methylene,        ethylene or prop-2-yn-1-ylene);    -   1.14 Formula 1.13, wherein D is methylene;    -   1.15 Any of formulae 1.12-1.14, wherein E is a single bond,        C₂₋₄alkynylene (e.g., —C≡C—), arylene (e.g., phenylene) or        heteroarylene (e.g., pyridylene);    -   1.16 Any of formulae 1.12-1.14, wherein E is arylene (e.g.,        phenylene);    -   1.17 Any of formulae 1.12-1.14, wherein E is phenylene;    -   1.18 Any of formulae 1.12-1.14, wherein E is heteroarylene        (e.g., pyridylene);    -   1.19 Any of formulae 1.12-1.14, wherein E is phenylene wherein F        is para-substituted;    -   1.20 Any of formulae 1.12-1.14, wherein E is heteroarylene        (e.g., pyridylene);    -   1.21 Any of formulae 1.12-1.14, wherein E is a single bond;    -   1.22 Any of formulae 1.12-1.21, wherein F: is H, aryl (e.g.,        phenyl), heteroaryl (e.g., pyridyl, e.g., pyrid-2-yl), halo        (e.g., F, Br, Cl), haloC₁₋₆alkyl (e.g., trifluoromethyl),        C₁₋₆alkoxy (e.g., methoxy), —C(O)—R₁₅, —N(R₁₆)(R₁₇), or        C₃₋₇cycloalkyl optionally containing at least one atom selected        from a group consisting of N or O (e.g., cyclopentyl,        cyclohexyl, pyrrolidinyl (e.g., pyrrolidin-3-yl or        pyrrolidin-2-yl), tetrahydro-2H-pyran-4-yl, or morpholinyl)        optionally substituted with one or more halo (e.g., F, Cl or        Br), C₁₋₆alkyl (e.g., methyl), haloC₁₋₆alkyl (e.g.,        trifluoromethyl);    -   1.23 Formula 1.22, wherein F is haloC₁₋₆alkyl (e.g.,        trifluoromethyl);    -   1.24 Formula 1.22, wherein F is trifluoromethyl;    -   1.25 Formula 1.22, wherein F is halo (e.g., F, Br, Cl);    -   1.26 Formula 1.22, wherein F is Cl;    -   1.27 Formula 1.22, wherein F is C₁₋₆alkoxy (e.g., methoxy);    -   1.28 Formula 1.22, wherein F is heteroaryl (e.g., pyridyl, e.g.,        pyrid-2-yl);    -   1.29 Formula 1.22, wherein F is pyridyl;    -   1.30 Formula 1.22, wherein F is pyrid-2-yl;    -   1.31 Formula 1.22, wherein F is C₃₋₇cycloalkyl optionally        containing at least one atom selected from a group consisting of        N or O (e.g., cyclopentyl, cyclohexyl, pyrrolidinyl (e.g.,        pyrrolidin-3-yl), tetrahydro-2H-pyran-4-yl, morpholinyl);    -   1.32 Formula 1.22, wherein F is cyclohexyl;    -   1.33 Formula 1.22, wherein F is pyrrolidinyl (e.g.,        pyrrolidin-3-yl or pyrrolidin-2-yl) optionally substituted with        C₁₋₆alkyl (e.g., methyl), for example 1-methylpyrrolidin-2-yl;    -   1.34 Formula 1.22, wherein F is cyclopentyl;    -   1.35 Formula 1.22, wherein F is tetrahydro-2H-pyran-4-yl;    -   1.36 Formula 1.22, wherein F is aryl (e.g., phenyl);    -   1.37 Formula 1.22, wherein F is phenyl;    -   1.38 Formula 1.22, wherein F is 4-fluorophenyl;    -   1.39 Formula 1.22, wherein F is —C(O)—R₁₅ and R₁₅ is C₁₋₆alky        (e.g., methyl), haloC₁₋₆alkyl (e.g., trifluoromethyl), —OH or        —OC₁₋₆alkyl (e.g., —OCH₃);    -   1.40 Any of formulae 1.12-1.39, wherein D, E and F are        independently and optionally substituted with one or more halo        (e.g., F, Cl or Br), C₁₋₆alkyl (e.g., methyl), haloC₁₋₆alkyl        (e.g., trifluoromethyl), for example, F is heteroaryl, e.g.,        pyridyl substituted with one or more halo (e.g.,        6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,        3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl),        haloC₁₋₆alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or C₁₋₆alkyl        (e.g., 5-methylpyrid-2-yl), or F is aryl, e.g., phenyl,        substituted with one or more halo (e.g., 4-fluorophenyl), or F        is a C₃₋₇heterocycloalkyl (e.g., pyrrolidinyl) optionally        substituted with a C₁₋₆alkyl (e.g., 1-methylpyrrolidin-3-yl or        1-methylpyrrolidin-2-yl);    -   1.41 Formula 1.40, wherein F is substituted with one or more        halo (e.g., F, Cl or Br), C₁₋₆alkyl (e.g., methyl),        haloC₁₋₆alkyl (e.g., trifluoromethyl);    -   1.42 Formula 1.40, wherein F is 6-fluoropyrid-2-yl;    -   1.43 Formula 1.40, wherein F is 3-fluoropyrid-2-yl;    -   1.44 Formula 1.40, wherein F is 4-fluoropyrid-2-yl;    -   1.45 Formula 1.40, wherein F is 5-fluoropyrid-2-yl;    -   1.46 Formula 1.40, wherein F is heteroaryl, e.g., pyridyl,        optionally substituted with one or more haloC₁₋₆alkyl (e.g.,        5-trifluoromethylpyrid-2-yl;    -   1.47 Formula 1.40, wherein F is 5-trifluoromethylpyrid-2-yl;    -   1.48 Formula 1.40, wherein F is heteroaryl, e.g., pyridyl,        optionally substituted with one or more C₁₋₆alkyl (e.g.,        5-methylpyrid-2-yl);    -   1.49 Formula 1.40, wherein F is 5-methylpyrid-2-yl;    -   1.50 Formula 1.22, wherein F is —C(O)—R₁₅ and R₁₅ is methyl;    -   1.51 Formula 1.22, wherein F is —C(O)—R₁₅ and R₁₅ is        trifluoromethyl;    -   1.52 Formula 1.22, wherein F is —C(O)—R₁₅ and R₁₅ is —OH;    -   1.53 Formula 1.22, wherein F is —C(O)—R₁₅ and R₁₅ is —OC₁₋₆alkyl        (e.g., —OCH₃);    -   1.54 Formula 1.22, wherein F is —C(O)—R₁₅ and R₁₅ is —OCH₃;    -   1.55 Formula 1.22, wherein F is —N(R₁₆)(R₁₇);    -   1.56 Formula II-A or II-B or any of 1.1-1.11, wherein R₅ is a        substituted heteroarylalkyl, e.g., substituted with haloalkyl;    -   1.57 Formula II-A or II-B or any of 1.1-1.11, wherein R₅ is        attached to one of the nitrogens on the pyrazolo portion of        Formula II-A or II-B and is a moiety of Formula A

-   -   -   wherein X, Y and Z are, independently, N or C, and R₈, R₉,            R₁₁ and R₁₂ are independently H or halogen (e.g., Cl or F),            and R₁₀ is halogen, C₁₋₆alkyl, C₁₋₆alkoxy (e.g., methoxy),            C₃₋₇cycloalkyl, heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl or            piperidinyl), C₁₋₆haloalkyl (e.g., trifluoromethyl), aryl            (e.g., phenyl), heteroaryl (e.g., pyridyl (for example            pyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)),            diazolyl, triazolyl, tetrazolyl, arylcarbonyl (e.g.,            benzoyl), C₁₋₆alkylsulfonyl (e.g., methylsulfonyl),            heteroarylcarbonyl, or C₁₋₆alkoxycarbonyl; provided that            when X, Y, or Z is nitrogen, R₈, R₉, or R₁₀, respectively,            is not present

    -   1.58 Formula 1.57, wherein R₅ is a substituted heteroarylmethyl,        e.g., para-substituted with haloalkyl;

    -   1.59 Formula 1.57, wherein R₅ is a moiety of Formula A wherein        R₈, R₉, R₁₁, and R₁₂ are H and R₁₀ is phenyl;

    -   1.60 Formula 1.57, wherein R₅ is a moiety of Formula A wherein        R₈, R₉, R₁₁, and R₁₂ are H and R₁₀ is pyridyl or thiadiazolyl;

    -   1.61 Formula 1.57, wherein R₅ is a moiety of Formula A wherein        R₈, R₉, R₁₁, and R₁₂ are H and R₁₀ is pyridyl optionally        substituted with halo (e.g., 6-fluoropyrid-2-yl);

    -   1.62 Formula 1.57, wherein R₅ is a moiety of Formula A wherein        R₈, R₉, R₁₁, and R₁₂ are, independently, H or halogen, and R₁₀        is haloalkyl;

    -   1.63 Formula 1.57, wherein R₅ is a moiety of Formula A wherein        R₈, R₉, R₁₁, and R₁₂ are, independently, H, and R₁₀ is        C₁₋₆alkylsulfonyl;

    -   1.64 Formula II-A or II-B or any of 1.1-1.63, wherein R₆ is        -   C₁₋₆alkyl (e.g., isopropyl),        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or        -   arylC₁₋₆alkyl (e.g., benzyl),        -   wherein the aryl or heteroaryl is optionally substituted            with one or more group selected from halo (e.g., F, Cl),            hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl, for            example, R₆ is 3-chlorophenyl or 4-fluorophenyl;

    -   1.65 Formula 1.64, wherein R₆ is aryl (e.g., phenyl) optionally        substituted with one or more halo (e.g., F, Cl), hydroxy or        C₁₋₆alkoxy;

    -   1.66 Formula 1.64, wherein R₆ is aryl (e.g., phenyl) optionally        substituted with halo (e.g., 4-fluorophenyl);

    -   1.67 Formula 1.64, wherein R₆ is C₁₋₆alkyl;

    -   1.68 Formula 1.64, wherein R₆ is C₃₋₇cycloalkyl (e.g.,        cyclopentyl);

    -   1.69 Formula 1.64, wherein R₆ is phenyl or fluorophenyl (e.g.,        4-fluorophenyl);

    -   1.70 Formula II-A or II-B or any of 1.1-1.69, wherein R₇ is H,        C₁₋₆alkyl (e.g., methyl), halogen, —N(R_(is))(R₁₉);

    -   1.71 Formula 1.70, wherein R₇ is H,

    -   1.72 Formula 1.70, wherein R₇ is C₁₋₆alkyl (e.g., methyl);

    -   1.73 Formula 1.70, wherein R₇ is methyl;

    -   1.74 Formula 1.70, wherein R₇ is ethyl;

    -   1.75 Formula II-A or II-B or any of 1.1-1.74, wherein n=0;

    -   1.76 Formula II-A or II-B or any of 1.1-1.74, wherein n=1;

    -   1.77 Formula 1.76, wherein n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃        and R₁₄, are, independently, H or C₁₋₆alkyl, aryl, heteroaryl,        (optionally hetero)arylC₁₋₆alkoxy or (optionally        hetero)arylC₁₋₆alkyl;

    -   1.78 any of the preceding formulae wherein the compound is        Formula I-A;

    -   1.79 any of the preceding formulae wherein R₁₆ and R₁₇ are        independently H or C₁₋₆alkyl;

    -   1.80 any of the preceding formulae wherein R₁₈ and R₁₉ are        independently        -   H,        -   C₁₋₆alky (e.g., methyl, ethyl, n-propyl, isobutyl),        -   C₃₋₈cycloalkyl (e.g., cyclohexyl or cyclopentyl),        -   heteroC₃₋₈cycloalkyl (e.g., pyrrolidinyl, piperidinyl,            morpholinyl),        -   aryl (e.g., phenyl) or        -   heteroaryl (e.g., pyridyl),        -   wherein said aryl and heteroaryl are optionally substituted            with one or more            -   halo (e.g., fluorophenyl, e.g., 4-fluorophenyl),            -   hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or                2-hydroxyphenyl),            -   C₁₋₆alkyl (e.g., methyl),            -   haloC₁₋₆alkyl (e.g., trifluoromethyl),            -   carboxy, or            -   an additional aryl, heteroaryl (e.g., biphenyl or                pyridylphenyl) or C₃₋₈cycloalkyl;

    -   1.81 any of the preceding formulae wherein R₂₀ is H, C₁₋₆alkyl        or C₃₋₇cycloalkyl;

    -   1.82 any of the preceding formulae wherein R₂₀ is H,

    -   1.83 any of the preceding formulae wherein the compound is:

-   -   1.84 any of the preceding formulae wherein the compounds inhibit        phosphodiesterase-mediated (e.g., PDE1-mediated, especially        PDE1B-mediated) hydrolysis of cGMP, e.g., with an IC₅₀ of less        than 1 μM, preferably less than 750 nM, more preferably less        than 500 nM, more preferably less than 50 nM in an        immobilized-metal affinity particle reagent PDE assay, for        example, as described in Example 2,    -   in free or salt form.

In a further embodiment, the Compound of Formula II-A or II-B as definedabove is a Compound of Formula III-A or III-B, wherein:

-   -   (i) Q is C(═O), C(═S), C(═N(R₂₀)) or CH₂;    -   (ii) L is —O—;    -   (iii) R₁ is H or C₁₋₆ alkyl (e.g., methyl);    -   (iv) R₄ is H or C₁₋₆ alkyl (e.g., methyl or isopropyl) and R₂        and R₃ are, independently,        -   H        -   C₁₋₆alkyl (e.g., methyl, isopropyl) optionally substituted            with halo or hydroxy (e.g., R₂ and R₃ are both methyl, or R₂            is H and R₃ is methyl, ethyl, isopropyl or hydroxyethyl),        -   aryl,        -   heteroaryl,        -   (optionally hetero)arylalkoxy,        -   (optionally hetero)arylC₁₋₆alkyl, or        -   R₂ and R₃ together form a 3-6-membered ring;    -   or    -   R₂ is H and R₃ and R₄ together form a di-, tri- or        tetramethylene bridge (pref. wherein the R₃ and R₄ together have        the cis configuration, e.g.,    -   where the carbons carrying R₃ and R₄ have the R and S        configurations, respectively);    -   (v) R₅ is        -   a) -D-E-F, wherein:            -   D is C₁₋₆alkylene (e.g., methylene, ethylene or                prop-2-yn-1-ylene);            -   E is a single bond, C₂₋₄alkynylene (e.g., —C≡C—),                arylene (e.g., phenylene) or heteroarylene (e.g.,                pyridylene);            -   F is                -   H,                -   aryl (e.g., phenyl),                -   heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for                    example, pyrid-2-yl, imidazol-1-yl,                    1,2,4-triazol-1-yl),                -   halo (e.g., F, Br, Cl),                -   haloC₁₋₆alkyl (e.g., trifluoromethyl),                -   C₁₋₆alkoxy (e.g., methoxy),                -   —C(O)—R₁₅,                -   —N(R₁₆)(R₁₇), or                -   C₃₋₇cycloalkyl optionally containing at least one                    atom selected from a group consisting of N or O                    (e.g., cyclopentyl, cyclohexyl, pyrrolidinyl (e.g.,                    pyrrolidin-3-yl), tetrahydro-2H-pyran-4-yl, or                    morpholinyl);            -   wherein D, E and F are independently and optionally                substituted with one or more halo (e.g., F, Cl or Br),                C₁₋₆alkyl (e.g., methyl), haloC₁₋₆alkyl (e.g.,                trifluoromethyl), C₁₋₆alkoxy (e.g., methoxy), hydroxy,                C₁₋₆-carboxy, or an additional aryl or heteroaryl (e.g.,                biphenyl or pyridylphenyl),            -   for example, F is heteroaryl, e.g., pyridyl substituted                with one or more halo (e.g., 6-fluoropyrid-2-yl,                5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,                3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl,                4,6-dichloropyrid-2-yl), haloC₁₋₆alkyl (e.g.,                5-trifluoromethylpyrid-2-yl) or C₁₋₆alkyl (e.g.,                5-methylpyrid-2-yl), or F is aryl, e.g., phenyl,                substituted with one or more halo (e.g., 4-fluorophenyl)                or F is a C₃₋₇heterocycloalkyl (e.g., pyrrolidinyl)                optionally substituted with a C₁₋₆alkyl (e.g.,                1-methylpyrrolidin-3-yl or 1-methylpyrrolidin-2-yl); or        -   b) a substituted heteroarylalkyl, e.g., substituted with            haloC₁₋₆alkyl;        -   c) attached to the nitrogen on the pyrrolo portion of            Formula III-A or III-B and is a moiety of Formula A

-   -   -   -   wherein X, Y and Z are, independently, N or C, and R₈,                R₉, R₁₁ and R₁₂ are independently H or halogen (e.g., Cl                or F), and R₁₀ is                -   halogen,                -   C₁₋₆alkyl,                -   haloC₁₋₆alkyl (e.g., trifluoromethyl)                -   C₁₋₆alkoxy (e.g. methoxy),                -   C₃₋₇cycloalkyl,                -   heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl or                    piperidinyl),                -   hetero                -   C₁₋₆haloalkyl (e.g., trifluoromethyl),                -   aryl (e.g., phenyl),                -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl or                    pyrid-4-yl), or thiadiazolyl (e.g.,                    1,2,3-thiadiazol-4-yl)), diazolyl (e.g.,                    imidazol-1-yl), triazolyl (e.g.,                    1,2,4-triazol-1-yl), tetrazolyl,                -   arylcarbonyl (e.g., benzoyl),                -   alkylsulfonyl (e.g., methylsulfonyl),                -   heteroarylcarbonyl, or                -   alkoxycarbonyl;            -   wherein the aryl, heteroaryl, cycloalkyl or                heterocycloalkyl is independently, optionally                substituted with one or more C₁₋₆alkyl (e.g., methyl),                halogen (e.g., chloro or fluoro), haloC₁₋₆alkyl (e.g.,                trifluoromethyl), hydroxy, C₁₋₆-carboxy, —SH or an                additional aryl or heteroaryl (e.g., biphenyl or                pyridylphenyl),            -   provided that when X, Y, or Z is nitrogen, R₈, R₉, or                R₁₀, respectively, is not present;

    -   (vi) R₆ is        -   C₁₋₆alkyl (e.g., isopropyl),        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or            arylC₁₋₆alkyl (e.g., benzyl),        -   wherein the aryl or heteroaryl is optionally substituted            with one or more group selected from halo (e.g., F, Cl),            hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl, for            example, R₆ is 3-chlorophenyl or 4-fluorophenyl;

    -   (vii) R₇ is H, C₁₋₆alkyl (e.g., methyl or ethyl), halogen (e.g.,        Cl), —N(R₁₈)(R₁₉), hydroxy or C₁₋₆alkoxy;

    -   (viii) n=0 or 1;

    -   (ix) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,        independently, H or C₁₋₆alkyl, aryl, heteroaryl, (optionally        hetero)arylC₁₋₆alkoxy, (optionally hetero)arylC₁₋₆alkyl or R₁₄        can form a bridge with R₂ or R₄;

    -   (x) R₁₅ is —OH or —OC₁₋₆alkyl (e.g., —OCH₃);

    -   (xi) R₁₆ and R₁₇ are independently H or C₁₋₆alkyl;

    -   (xii) R₁₈ and R₁₉ are independently H, C₁₋₆alky (e.g., methyl,        ethyl, n-propyl, isobutyl), C₃₋₈cycloalkyl (e.g., cyclohexyl or        cyclopenyl), heteroC₃₋₈cycloalkyl (e.g., pyrrolidinyl,        piperidinyl, morpholinyl), aryl (e.g., phenyl) or heteroaryl,        wherein said aryl and heteroaryl are optionally substituted with        one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl),        hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or        2-hydroxyphenyl) C₁₋₆alkyl (e.g., methyl), haloC₁₋₆alkyl (e.g.,        trifluoromethyl), C₁₋₆-carboxy, or an additional aryl,        heteroaryl (e.g., biphenyl or pyridylphenyl) or C₃₋₈cycloalkyl;

    -   (xiii) R₂₀ is H, C₁₋₆alkyl or C₃₋₇cycloalkyl;        in free or salt form.

In still another embodiment, the Compound of Formula II-A or II-B asdefined above is a Compound of Formula IV-A or IV-B, wherein:

-   -   (i) Q is C(═O), C(═S), C(═N(R₂₀)) or CH₂;    -   (ii) L is —O—;    -   (iii) R₁ is H or C₁₋₆ alkyl (e.g., methyl);    -   (iv) R₄ is H or C₁₋₆ alkyl (e.g., methyl or isopropyl) and R₂        and R₃ are, independently,        -   H        -   C₁₋₆alkyl (e.g., methyl, isopropyl) optionally substituted            with halo or hydroxy (e.g., R₂ and R₃ are both methyl, or R₂            is H and R₃ is methyl, ethyl, isopropyl or hydroxyethyl),        -   aryl,        -   heteroaryl,        -   (optionally hetero)arylalkoxy,        -   (optionally hetero)arylC₁₋₆alkyl, or        -   R₂ and R₃ together form a 3- to 6-membered ring;    -   or        -   R₂ is H and R₃ and R₄ together form a di-, tri- or            tetramethylene bridge (pref. wherein the R₃ and R₄ together            have the cis configuration, e.g., where the carbons carrying            R₃ and R₄ have the R and S configurations, respectively);    -   (v) R₅ is attached to the nitrogen on the pyrrolo portion of        Formula IV-A or IV-B and is a moiety of Formula A

-   -   -   wherein X, Y and Z are, independently, N or C, and R₈, R₉,            R₁₁ and R₁₂ are independently H or halogen (e.g., Cl or F),            and R₁₀ is            -   halogen,            -   C₁₋₆alkyl,            -   C₁₋₆alkoxy (e.g., methoxy),            -   haloC₁₋₆alkyl (e.g., trifluoromethyl)            -   C₁₋₆alkoxy (e.g. methoxy),            -   C₃₋₇cycloalkyl,            -   heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl or                piperidinyl),            -   C₁₋₆haloalkyl (e.g., trifluoromethyl),            -   aryl (e.g., phenyl),            -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl or                pyrid-4-yl), or thiadiazolyl (e.g.,                1,2,3-thiadiazol-4-yl)), diazolyl (e.g., imidazol-1-yl),                triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl,            -   arylcarbonyl (e.g., benzoyl),            -   C₁₋₆alkylsulfonyl (e.g., methylsulfonyl),            -   heteroarylcarbonyl, or            -   C₁₋₆alkoxycarbonyl;        -   wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl            is independently, optionally substituted with one or more            C₁₋₆alkyl (e.g., methyl), halogen (e.g., chloro or fluoro),            haloC₁₋₆alkyl (e.g., trifluoromethyl), hydroxy,            C₁₋₆-carboxy, —SH or an additional aryl or heteroaryl (e.g.,            biphenyl or pyridylphenyl),        -   provided that when X, Y, or Z is nitrogen, R₈, R₉, or R₁₀,            respectively, is not present;

    -   (vi) R₆ is        -   C₁₋₆alkyl (e.g., isopropyl),        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or        -   arylC₁₋₆alkyl (e.g., benzyl),        -   wherein the aryl or heteroaryl is optionally substituted            with one or more group selected from halo (e.g., F, Cl),            hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl, for            example, R₆ is 3-chlorophenyl or 4-fluorophenyl;

    -   (vii) R₇ is H;

    -   (viii) n=0 or 1;

    -   (ix) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,        independently, H or C₁₋₆alkyl, aryl, heteroaryl, (optionally        hetero)arylC₁₋₆alkoxy, (optionally hetero)arylC₁₋₆alkyl or R₁₄        can form a bridge with R₂ or R₄;

    -   (x) R₂₀ is H, C₁₋₆alkyl or C₃₋₇cycloalkyl;        in free or salt form.

In yet another embodiment, the Compound of Formula II-A or II-B asdefined above is a Compound of Formula V-A or V-B, wherein:

-   -   (i) Q is C(═O);    -   (ii) L is —O—;    -   (iii) R₁ is H or C₁₋₆ alkyl (e.g., methyl);    -   (iv) R₄ is H or C₁₋₆ alkyl (e.g., methyl or isopropyl) and R₂        and R₃ are, independently,        -   H        -   C₁₋₆alkyl (e.g., methyl, isopropyl) optionally substituted            with halo or hydroxy (e.g., R₂ and R₃ are both methyl, or R₂            is H and R₃ is methyl, ethyl, isopropyl or hydroxyethyl),        -   aryl,        -   heteroaryl,        -   (optionally hetero)arylalkoxy,        -   (optionally hetero)arylC₁₋₆alkyl, or        -   R₂ and R₃ together form a 3- to 6-membered ring;    -   or    -   R₂ is H and R₃ and R₄ together form a di-, tri- or        tetramethylene bridge (pref. wherein the R₃ and R₄ together have        the cis configuration, e.g., where the carbons carrying R₃ and        R₄ have the R and S configurations, respectively);    -   (v) R₅ is attached to the nitrogen on the pyrrolo portion of        Formula V-A or V-B and is a moiety of Formula A

-   -   -   wherein X, Y and Z are, independently, N or C, and R₈, R₉,            R₁₁ and R₁₂ are independently H or halogen (e.g., Cl or F),            and R₁₀ is C₁₋₆alkoxy (e.g., methoxy),            -   C₃₋₇cycloalkyl,            -   heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl or                piperidinyl),            -   aryl (e.g., phenyl),            -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl or                pyrid-4-yl), or thiadiazolyl (e.g.,                1,2,3-thiadiazol-4-yl)), diazolyl (e.g., imidazol-1-yl),                triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl,        -   wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl            is independently, optionally substituted with one or more            C₁₋₆alkyl (e.g., methyl), halogen (e.g., chloro or fluoro),            haloC₁₋₆alkyl (e.g., trifluoromethyl), hydroxy,            C₁₋₆-carboxy, —SH or an additional aryl or heteroaryl (e.g.,            biphenyl or pyridylphenyl),        -   provided that when X, Y, or Z is nitrogen, R₈, R₉, or R₁₀,            respectively, is not present;

    -   (vi) R₆ is        -   C₁₋₆alkyl (e.g., isopropyl),        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or        -   arylC₁₋₆alkyl (e.g., benzyl),        -   wherein the aryl or heteroaryl is optionally substituted            with one or more group selected from halo (e.g., F, Cl),            hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl, for            example, R₆ is 3-chlorophenyl or 4-fluorophenyl;

    -   (vii) R₇ is H;

    -   (viii) n=0 or 1; and

    -   (ix) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,        independently, H or C₁₋₆alkyl, aryl, heteroaryl, (optionally        hetero)arylC₁₋₆alkoxy, (optionally hetero)arylC₁₋₆alkyl or R₁₄        can form a bridge with R₂ or R₄;        in free or salt form.

In yet another embodiment, the Compound of Formula II-A or II-B asdefined above is a Compound of Formula VI-A or VI-B, wherein:

-   -   (i) Q is C(═O);    -   (ii) L is —O—;    -   (iii) R₁ is H or C₁₋₆ alkyl (e.g., methyl);    -   (iv) R₄ is H or C₁₋₆ alkyl (e.g., methyl or isopropyl) and R₂        and R₃ are, independently,        -   H        -   C₁₋₆alkyl (e.g., methyl, isopropyl) optionally substituted            with halo or hydroxy (e.g., R₂ and R₃ are both methyl, or R₂            is H and R₃ is methyl, ethyl, isopropyl or hydroxyethyl),        -   aryl,        -   heteroaryl,        -   (optionally hetero)arylalkoxy,        -   (optionally hetero)arylC₁₋₆alkyl, or        -   R₂ and R₃ together form a 3- to 6-membered ring;    -   or    -   R₂ is H and R₃ and R₄ together form a di-, tri- or        tetramethylene bridge (pref. wherein the R₃ and R₄ together have        the cis configuration, e.g., where the carbons carrying R₃ and        R₄ have the R and S configurations, respectively);    -   (v) R₅ is attached to the nitrogen on the pyrrolo portion of        Formula IV-A or IV-B and is a moiety of Formula A

-   -   -   wherein X, Y and Z are, independently, N or C, and R₈, R₉,            R₁₁ and        -   R₁₂ are independently H or halogen (e.g., Cl or F), and R₁₀            is            -   C₁₋₆alkoxy (e.g., methoxy),            -   C₃₋₇cycloalkyl,            -   heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl or                piperidinyl),            -   aryl (e.g., phenyl),            -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl or                pyrid-4-yl), or thiadiazolyl (e.g.,                1,2,3-thiadiazol-4-yl)), diazolyl (e.g., imidazol-1-yl),                triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl,        -   wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl            is independently, optionally substituted with one or more            C₁₋₆alkyl (e.g., methyl), halogen (e.g., chloro or fluoro),            haloC₁₋₆alkyl (e.g., trifluoromethyl), hydroxy,            C₁₋₆-carboxy, —SH or an additional aryl or heteroaryl (e.g.,            biphenyl or pyridylphenyl),        -   provided that when X, Y, or Z is nitrogen, R₈, R₉, or R₁₀,            respectively, is not present;

    -   (vi) R₆ is        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or        -   wherein the aryl or heteroaryl is optionally substituted            with one or more group selected from halo (e.g., F, CO,            hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl, for            example, R₆ is 3-chlorophenyl or 4-fluorophenyl;

    -   (vii) R₇ is H;

    -   (viii) n=0 or 1; and

    -   (ix) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,        independently, H or C₁₋₆alkyl, aryl, heteroaryl, (optionally        hetero)arylC₁₋₆alkoxy, (optionally hetero)arylC₁₋₆alkyl or R₁₄        can form a bridge with R₂ or R₄;        in free or salt form.

In yet another embodiment, the Compound of Formula II-A or II-B asdefined above is a Compound of Formula VII-A or VII-B, wherein:

-   -   (i) Q is C(═O);    -   (ii) L is —O—;    -   (iii) R₁ is H or C₁₋₆ alkyl (e.g., methyl);    -   (iv) R₂ is H and R₃ and R₄ together form a di-, tri- or        tetramethylene bridge (pref. wherein the R₃ and R₄ together have        the cis configuration, e.g., where the carbons carrying R₃ and        R₄ have the R and S configurations, respectively);    -   (v) R₅ is attached to the nitrogen on the pyrrolo portion of        Formula VII-A or VII-B and is a moiety of Formula A

-   -   -   wherein X, Y and Z are, independently, N or C, and R₈, R₉,            R₁₁ and R₁₂ are independently H or halogen (e.g., Cl or F),            and R₁₀ is            -   C₁₋₆alkoxy (e.g., methoxy),            -   C₃₋₇cycloalkyl,            -   heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl or                piperidinyl),            -   aryl (e.g., phenyl),            -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl or                pyrid-4-yl), or thiadiazolyl (e.g.,                1,2,3-thiadiazol-4-yl)), diazolyl (e.g., imidazol-1-yl),                triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl,            -   wherein the aryl, heteroaryl, cycloalkyl or                heterocycloalkyl is independently, optionally                substituted with one or more C₁₋₆alkyl (e.g., methyl),                halogen (e.g., chloro or fluoro), haloC₁₋₆alkyl (e.g.,                trifluoromethyl), hydroxy, C₁₋₆-carboxy, —SH or an                additional aryl or heteroaryl (e.g., biphenyl or                pyridylphenyl),            -   provided that when X, Y, or Z is nitrogen, R₈, R₉, or                R₁₀, respectively, is not present;

    -   (vi) R₆ is        -   C₁₋₆alkyl (e.g., isopropyl),        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or        -   arylC₁₋₆alkyl (e.g., benzyl),        -   wherein the aryl or heteroaryl is optionally substituted            with one or more group selected from halo (e.g., F, Cl),            hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl, for            example, R₆ is 3-chlorophenyl or 4-fluorophenyl;

    -   (vii) R₇ is H;

    -   (viii) n=0 or 1; and

    -   (ix) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,        independently, H or C₁₋₆alkyl, aryl, heteroaryl, (optionally        hetero)arylC₁₋₆alkoxy, (optionally hetero)arylC₁₋₆alkyl or R₁₄        can form a bridge with R₂ or R₄;        in free or salt form.

In yet another embodiment, the Compound of Formula II-A or II-B asdefined above is a Compound of Formula VIII-A or VIII-B, wherein:

-   -   (i) Q is C(═O);    -   (ii) L is —O—;    -   (iii) R₁ is H or C₁₋₆ alkyl (e.g., methyl);    -   (iv) R₂ is H and R₃ and R₄ together form a di-, tri- or        tetramethylene bridge (pref. wherein the R₃ and R₄ together have        the cis configuration, e.g., where the carbons carrying R₃ and        R₄ have the R and S configurations, respectively);    -   (v) R₅ is attached to the nitrogen on the pyrrolo portion of        Formula VIII-A or VIII-B and is a moiety of Formula A

-   -   -   wherein X, Y and Z are, C; R₈, R₉, R₁₁ and R₁₂ are H; and            R₁₀ is            -   heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl or                piperidinyl),            -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl or                pyrid-4-yl), or thiadiazolyl (e.g.,                1,2,3-thiadiazol-4-yl)), diazolyl (e.g., imidazol-1-yl),                triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl,        -   wherein the heteroaryl or heterocycloalkyl is independently,            optionally substituted with one or more C₁₋₆alkyl (e.g.,            methyl), halogen (e.g., chloro or fluoro),

    -   (vi) R₆ is        -   C₁₋₆alkyl (e.g., isopropyl),        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or        -   arylC₁₋₆alkyl (e.g., benzyl),        -   wherein the aryl or heteroaryl is optionally substituted            with one or more group selected from halo (e.g., F, CO,            hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl, for            example, R₆ is 3-chlorophenyl or 4-fluorophenyl;

    -   (vii) R₇ is H;

    -   (viii) n=0 or 1; and

    -   (ix) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,        independently, H or C₁₋₆alkyl, aryl, heteroaryl, (optionally        hetero)arylC₁₋₆alkoxy, (optionally hetero)arylC₁₋₆alkyl or R₁₄        can form a bridge with R₂ or R₄;        in free or salt form.

In yet another embodiment, the Compound of Formula II-A or II-B asdefined above is a Compound of Formula IX-A or IX-B, wherein:

-   -   (i) Q is C(═O);    -   (ii) L is —O—;    -   (iii) R₁ is H or C₁₋₆ alkyl (e.g., methyl);    -   (iv) R₂ is H and R₃ and R₄ together form a di-, tri- or        tetramethylene bridge (pref. wherein the R₃ and R₄ together have        the cis configuration, e.g., where the carbons carrying R₃ and        R₄ have the R and S configurations, respectively);    -   (v) R₅ is attached to the nitrogen on the pyrrolo portion of        Formula IX-A or IX-B and is a moiety of Formula A

-   -   -   wherein X, Y and Z are, C; R₈, R₉, R₁₁ and R₁₂ are H; and            R₁₀ is selected from the following: pyrrolidinyl,            piperidinyl, pyridyl (for example pyrid-2-yl or pyrid-4-yl),            thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl (e.g.,            imidazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl),            tetrazolyl, wherein R₁₀ is optionally substituted with one            or more C₁₋₆alkyl (e.g., methyl), halogen (e.g., chloro or            fluoro), for example 6-fluoropyrid-2-yl or            1-methylpyrrolidin-2-yl;

    -   (vi) R₆ is        -   C₁₋₆alkyl (e.g., isopropyl),        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or        -   arylC₁₋₆alkyl (e.g., benzyl),        -   wherein the aryl or heteroaryl is optionally substituted            with one or more group selected from halo (e.g., F, Cl),            hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl, for            example, R₆ is 3-chlorophenyl or 4-fluorophenyl;

    -   (vii) R₇ is H;

    -   (viii) n=0 or 1; and

    -   (ix) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,        independently, H or C₁₋₆alkyl, aryl, heteroaryl, (optionally        hetero)arylC₁₋₆alkoxy, (optionally hetero)arylC₁₋₆alkyl or R₁₄        can form a bridge with R₂ or R₄;        in free or salt form.

In yet another embodiment, the Compound of Formula II-A or II-B asdefined above is a Compound of Formula X-A or X-B, wherein:

-   -   (i) Q is C(═O);    -   (ii) L is —O—;    -   (iii) R₁ is H or C₁₋₆ alkyl (e.g., methyl);    -   (iv) R₂ is H and R₃ and R₄ together form a di-, tri- or        tetramethylene bridge (pref. wherein the R₃ and R₄ together have        the cis configuration, e.g., where the carbons carrying R₃ and        R₄ have the R and S configurations, respectively);    -   (v) R₅ is attached to the nitrogen on the pyrrolo portion of        Formula X-A or X-B and is a moiety of Formula A

-   -   -   wherein X, Y and Z are, C; R₈, R₉, R₁₁ and R₁₂ are H; and            R₁₀ is pyrid-2-yl, 1,2,4-triazolyl, 6-fluoropyrid-2-yl or            1-methylpyrrolidin-2-yl;

    -   (vi) R₆ is        -   C₁₋₆alkyl (e.g., isopropyl),        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or        -   arylC₁₋₆alkyl (e.g., benzyl),        -   wherein the aryl or heteroaryl is optionally substituted            with one or more group selected from halo (e.g., F, CO,            hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl, for            example, R₆ is 3-chlorophenyl or 4-fluorophenyl;

    -   (vii) R₇ is H;

    -   (viii) n=0 or 1; and

    -   (ix) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,        independently, H or C₁₋₆alkyl, aryl, heteroaryl, (optionally        hetero)arylC₁₋₆alkoxy, (optionally hetero)arylC₁₋₆alkyl or R₁₄        can form a bridge with R₂ or R₄;        in free or salt form.

In still another embodiment, the Compound of Formula II-A or II-B asdefined above is a Compound of Formula XI-A or XI-B, wherein:

-   -   (i) Q is C(═O);    -   (ii) L is —O—;    -   (iii) R₁ is H or C₁₋₆ alkyl (e.g., methyl);    -   (iv) R₂ is H and R₃ and R₄ together form a di-, tri- or        tetramethylene bridge (pref. wherein the R₃ and R₄ together have        the cis configuration, e.g., where the carbons carrying R₃ and        R₄ have the R and S configurations, respectively);    -   (v) R₅ is attached to the nitrogen on the pyrrolo portion of        Formula XI-A or XI-B and is a moiety of Formula A

-   -   -   wherein X, Y and Z are, C; R₈, R₉, R₁₁ and R₁₂ are H; and            R₁₀ is C₁₋₆alkoxy (e.g. methoxy);

    -   (vi) R₆ is aryl (e.g., phenyl);

    -   (vii) R₇ is H;

    -   (viii) n=0,        in free or salt form.

In still another embodiment, the compound of the invention, e.g., any ofthe compounds hereinbefore described is preferably a Compound of FormulaII-A, III-A, IV-A, V-A, VI-A, VII-A, VIII-A, IX-A, X-A or XI-A.

If not otherwise specified or clear from context, the following termsherein have the following meanings:

-   -   (a) “Alkyl” as used herein is a saturated or unsaturated        hydrocarbon moiety, preferably saturated, preferably having one        to six carbon atoms, which may be linear or branched, and may be        optionally mono-, di- or tri-substituted, e.g., with halogen        (e.g., chloro or fluoro), hydroxy, or carboxy.    -   (b) “Cycloalkyl” as used herein is a saturated or unsaturated        nonaromatic hydrocarbon moiety, preferably saturated, preferably        comprising three to nine carbon atoms, at least some of which        form a nonaromatic mono- or bicyclic, or bridged cyclic        structure, and which may be optionally substituted, e.g., with        halogen (e.g., chloro or fluoro), hydroxy, or carboxy. Wherein        the cycloalkyl optionally contains one or more atoms selected        from N and O and/or S, said cycloalkyl may also be a        heterocycloalkyl.    -   (c) “Heterocycloalkyl” is, unless otherwise indicated, saturated        or unsaturated nonaromatic hydrocarbon moiety, preferably        saturated, preferably comprising three to nine carbon atoms, at        least some of which form a nonaromatic mono- or bicyclic, or        bridged cyclic structure, wherein at least one carbon atom is        replaced with N, O or S, which heterocycloalkyl may be        optionally substituted, e.g., with halogen (e.g., chloro or        fluoro), hydroxy, or carboxy.    -   (d) “Aryl” as used herein is a mono or bicyclic aromatic        hydrocarbon, preferably phenyl, optionally substituted, e.g.,        with alkyl (e.g., methyl), halogen (e.g., chloro or fluoro),        haloalkyl (e.g., trifluoromethyl), hydroxy, carboxy, or an        additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl).    -   (e) “Heteroaryl” as used herein is an aromatic moiety wherein        one or more of the atoms making up the aromatic ring is sulfur        or nitrogen rather than carbon, e.g., pyridyl or thiadiazolyl,        which may be optionally substituted, e.g., with alkyl, halogen,        haloalkyl, hydroxy or carboxy.    -   (f) For ease of reference, the atoms on the pyrazolo-pyrimidine        core of the Compounds of the Invention are numbered in        accordance with the numbering depicted in Formula I, unless        otherwise noted.    -   (g) Wherein E is phenylene, the numbering is as follows:

-   -   (h) It is intended that wherein the substituents end in “ene”,        for example, alkylene, phenylene or arylalkylene, said        substituents are intended to bridge or be connected to two other        substituents. Therefore, methylene is intended to be —CH₂— and        phenylene intended to be —C₆H₄— and arylalkylene is intended to        be —C₆H₄—CH₂— or —CH₂—C₆H₄—.    -   (i) The Compounds of the Invention are intended to be numbered        as follows:

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.Similarly, the substituents defined for the Compounds of the Inventionare intended to result in stable compounds.

Compounds of the Invention, e.g., substituted4,5,7,8-tetrahydro-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or4,5,7,8,9-pentahydro-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine, e.g.,Compounds of Formula II-A or II-B or any of formulae III-A or III-Bthrough XI-A or XI-B, or 1.1-1.84 may exist in free or salt form, e.g.,as acid addition salts. In this specification unless otherwiseindicated, language such as “Compounds of the Invention” is to beunderstood as embracing the compounds in any form, for example free oracid addition salt form, or where the compounds contain acidicsubstituents, in base addition salt form. The Compounds of the Inventionare intended for use as pharmaceuticals, therefore pharmaceuticallyacceptable salts are preferred. Salts which are unsuitable forpharmaceutical uses may be useful, for example, for the isolation orpurification of free Compounds of the Invention or theirpharmaceutically acceptable salts, are therefore also included. In aparticular embodiment, the salt of the compounds of the invention is aformic acid addition salt.

Compounds of the Invention may in some cases also exist in prodrug form.A prodrug form is compound which converts in the body to a Compound ofthe Invention. For example when the Compounds of the Invention containhydroxy or carboxy substituents, these substituents may formphysiologically hydrolysable and acceptable esters. As used herein,“physiologically hydrolysable and acceptable ester” means esters ofCompounds of the Invention which are hydrolysable under physiologicalconditions to yield acids (in the case of Compounds of the Inventionwhich have hydroxy substituents) or alcohols (in the case of Compoundsof the Invention which have carboxy substituents) which are themselvesphysiologically tolerable at doses to be administered. Therefore,wherein the Compound of the Invention contains a hydroxy group, forexample, Compound-OH, the acyl ester prodrug of such compound, forexample, Compound-O—C(O)—C₁₋₄alkyl, can hydrolyze in the body to formphysiologically hydrolysable alcohol (Compound-OH) on the one hand andacid on the other (e.g., HOC(O)—C₁₋₄alkyl). Alternatively, wherein theCompound of the Invention contains a carboxylic acid, for example,Compound-C(O)OH, the acid ester prodrug of such compound, for example,Compound-C(O)O—C₁₋₄alkyl can hydrolyze to form Compound-C(O)OH andHO—C₁₋₄alkyl. As will be appreciated the term thus embraces conventionalpharmaceutical prodrug forms.

The invention also provides methods of making the Compounds of theInvention and methods of using the Compounds of the Invention fortreatment of diseases and disorders as set forth below (especiallytreatment of diseases characterized by reduced dopamine D1 receptorsignaling activity, such as Parkinson's disease, Tourette's Syndrome,Autism, fragile X syndrome, ADHD, restless leg syndrome, depression,cognitive impairment of schizophrenia, narcolepsy and diseases that maybe alleviated by the enhancement of progesterone-signaling such asfemale sexual dysfunction), or a disease or disorder such as psychosisor glaucoma). This list is not intended to be exhaustive and may includeother diseases and disorders as set forth below.

In another embodiment, the invention further provides a pharmaceuticalcomposition comprising a Compound of the Invention, in free orpharmaceutically acceptable salt form, in admixture with apharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

Methods of Making Compounds of the Invention

The compounds of the Invention and their pharmaceutically acceptablesalts may be made using the methods as described and exemplified hereinand by methods similar thereto and by methods known in the chemical art.Such methods include, but not limited to, those described below. If notcommercially available, starting materials for these processes may bemade by procedures, which are selected from the chemical art usingtechniques which are similar or analogous to the synthesis of knowncompounds. Various starting materials and/or Compounds of the Inventionmay be prepared using methods described in PCT/US2009/06438 (WO2010/065148). All references cited herein are hereby incorporated byreference in their entirety.

The Compounds of the Invention include their enantiomers,diastereoisomers and racemates, as well as their polymorphs, hydrates,solvates and complexes. Some individual compounds within the scope ofthis invention may contain double bonds. Representations of double bondsin this invention are meant to include both the E and the Z isomer ofthe double bond. In addition, some compounds within the scope of thisinvention may contain one or more asymmetric centers. This inventionincludes the use of any of the optically pure stereoisomers as well asany combination of stereoisomers.

As will be appreciated by those skilled in the art, the Compounds of theInvention may exhibit keto-enol tautomerization. Therefore, theinvention as defined in the present invention is to be understood asembracing both the structures as setforth herewith and their tautomericforms.

It is also intended that the Compounds of the Invention encompass theirstable and unstable isotopes. Stable isotopes are nonradioactiveisotopes which contain one additional neutron compared to the abundantnuclides of the same species (i.e., element). It is expected that theactivity of compounds comprising such isotopes would be retained, andsuch compound would also have utility for measuring pharmacokinetics ofthe non-isotopic analogs. For example, the hydrogen atom at a certainposition on the Compounds of the Invention may be replaced withdeuterium (a stable isotope which is non-radioactive). Examples of knownstable isotopes include, but not limited to, deuterium, ¹³C, ¹⁵N, ¹⁸O.Alternatively, unstable isotopes, which are radioactive isotopes whichcontain additional neutrons compared to the abundant nuclides of thesame species (i.e., element), e.g., ¹²³I, ¹³¹I, ¹²⁵I, ¹¹C, ¹⁸F, mayreplace the corresponding abundant species, e.g., I, C and Frespectively. Another example of useful isotope of the compound of theinvention is the ¹¹C isotope. These radio isotopes are useful forradio-imaging and/or pharmacokinetic studies of the compounds of theinvention. Methods of making isotopes of PDE1 inhibitors disclosed in WO2011/043816, the contents of which are incorporated by reference intheir entirety, may be used for making the isotopes of the compounds ofthe current invention

Melting points are uncorrected and (dec) indicates decomposition.Temperature are given in degrees Celsius (° C.); unless otherwisestated, operations are carried out at room or ambient temperature, thatis, at a temperature in the range of 18-25° C. Chromatography meansflash chromatography on silica gel; thin layer chromatography (TLC) iscarried out on silica gel plates. NMR data is in the delta values ofmajor diagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as an internal standard. Conventionalabbreviations for signal shape are used. Coupling constants (J) aregiven in Hz. For mass spectra (MS), the lowest mass major ion isreported for molecules where isotope splitting results in multiple massspectral peaks Solvent mixture compositions are given as volumepercentages or volume ratios. In cases where the NMR spectra arecomplex, only diagnostic signals are reported.

Terms and abbreviations:

BuLi=n-butyllithium

Bu^(t)OH=tert-butyl alcohol,

CAN=ammonium cerium (IV) nitrate,

DIPEA=diisopropylethylamine,

DMF=N,N-dimethylforamide,

DMSO=dimethyl sulfoxide,

Et₂O=diethyl ether,

EtOAc=ethyl acetate,

equiv.=equivalent(s),

h=hour(s),

HPLC=high performance liquid chromatography,

LDA=lithium diisopropylamide

MeOH=methanol,

NBS=N-bromosuccinimide

NCS=N-chlorosuccinimide

NaHCO₃=sodium bicarbonate,

NH₄OH=ammonium hydroxide,

Pd₂(dba)₃=tris[dibenzylideneacetone]dipalladium(0)

PMB=p-methoxybenzyl,

POCl₃=phosphorous oxychloride,

SOCl₂=thionyl chloride,

TFA=trifluoroacetic acid,

THF=tetrahedrofuran.

The synthetic methods in this invention are illustrated below. Thesignificances for the R groups are as set forth above for formula II-Aor II-B unless otherwise indicated.

In an aspect of the invention, Compounds of the invention, e.g., aCompound of Formulae II-A and II-B or any of the formulae disclosedherein may be formed by reacting a compound of 1-A and 1-B respectivelywith for example a R₅—X in a solvent such as DMF and a base such asK₂CO₃ at room temperature or with heating:

wherein all the substituents are as defined previously; L is oxy (—O—);X is a leaving group such as a halogen, mesylate, or tosylate.

Alternatively, compounds II-A and II-B may be synthesized by reacting acompound of 1-C and 1-D respectively with for example a R₆-L-H in asolvent such as dioxane or in neat condition with heating:

wherein all the substituents are as defined previously; L is oxy (—O—);X is a leaving group such as a halogen group.

Compound 1-C, e.g., wherein Q is C(═O) and X is a chloro group, may beprepared by, e.g., reacting compound 1-E with a chlorinating reagentsuch as hexachloroethane in the presence of a strong base or lithiumreagent such as LiHMDS. Compound 1-D, e.g., wherein Q is C(═O) and X isa chloro group, may be prepared by, e.g., reacting compound 1-F with achlorinating reagent such NCS in a solvent such as CCl₄. Sometimes, R₅can be a protective group such as a para-methoxybenzyl (PMB) group.Under this circumstance, compound 1-C or 1-D with the PMB substituent asR₅ can be deprotected using a reagent such as TFA/TFMSA, and then reactswith a different R₅X under basic conditions for rapidly synthesizing 1-Cor 1-D analogs.

Compounds (I)-E and (I)-F may be formed by reacting a compound of 2-Aand 2-B respectively with for example a R₅—X in a solvent such as DMFand a base such as K₂CO₃ at room temperature or with heating:

wherein all the substituents are as defined previously; X is a leavinggroup such as a halogen group.

Intermediate 2, e.g., wherein Q is C(═O) may be prepared by, e.g.,reacting Intermediate 3 with a strong base such as sodium hydride and areagent such as TsCHR₇NC, e.g., toluenesulfonylmethyl isocyanide, in asolvent such as THF.

Intermediate 3 may be prepared by, e.g., reacting Intermediate 4 with adehydrating reagent such as diethyl azodicarboxylate in the presence ofphosphine ligand such as triphenylphosphine.

Intermediate 4 may be made, e.g., by reacting a compound of 5-A with anamino alcohol in the presence of a strong base, for example, DBU(1,8-Diazabicyclo[5.4.0]undec-7-ene),

wherein all the substituents are as defined previously; X is a leavinggroup such as a halogen or methylthio group.

Alternatively, intermediate 4 may be made, e.g., by reacting a compoundof 5-B with an amino alcohol in the presence of a strong base, forexample, DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene) and a coupling reagentsuch as BOP at room temperature.

The thione Compounds of the Invention, e.g., Compounds of Formula II-Aor II-B wherein Q is C(═S) may then be prepared by reacting theCompounds of the Invention wherein Q is C(═O) with P₄S₁₀ in a microwavevial in the presence of a base, e.g., pyridine, and heating the mixtureto an elevated temperature, e.g., in a microwave, e.g., to about 150° C.The imine compounds of the Invention, e.g., Compounds of Formula II-A orII-B, wherein Q is C(═N(R₂₀)) may in turn be converted from the thionederivative (i.e., Compounds of Formula II-A or II-B, respectively,wherein with Q is C(═S)), by reacting the thione derivative withNH₂(R₂₀) in the presence of HgCl₂, e.g., in a solvent such as THF, andheating the reaction mixture to an elevated temperature, e.g., in amicrowave, e.g., to about 110° C.

The Compounds of the Invention, e.g., Compounds of Formula II-A or II-B,wherein Q is C(R₁₄)(R₁₅) may also be prepared by reacting the ketonederivative, e.g., Formula II-A or II-B respectively, wherein Q is C(═O),with a reducing agent, e.g., diisobutylaluminum hydride (DIBAL-H),lithium aluminum hydride, sodium borohydride, preferably, DIBAL-H.

The invention thus provides methods of making Compounds of Formula II-Aor II-B, for example, comprising

-   -   (i) reacting Intermediate 1-A or 1-B, respectively, with a        compound of formula R₅—X wherein L is oxy (—O—) and X is a        leaving group, e.g., halogen, mesylate, or tosylate, R₅ is as        defined above in Formula II-A or II-B, e.g., under basic        conditions, for example:

Alternative methods of making the compounds of the invention,particularly constructing the bottom (imidazole) ring of compounds ofthe compounds of the invention, may be found in U.S. ProvisionalApplications 61/349,952, which discloses methods of making similar PDE1inhibitors, the contents of which provisional application areincorporated by reference in their entirety.

Methods of Using Compounds of the Invention

The Compounds of the Invention, any of the compounds disclosed hereine.g., any of Compounds of Formula II-A or II-B, e.g., any of 1.1-1.84,or any of III-A, III-B, IV-A, IV-B, V-A, V-B, VI-A, VI-B, VII-A, VII-B,VIII-A, VIII-B, IX-A, IX-B, X-A, X-B, in free or salt form are useful inthe treatment of diseases characterized by disruption of or damage tocAMP and cGMP mediated pathways, e.g., as a result of increasedexpression of PDE1 or decreased expression of cAMP and cGMP due toinhibition or reduced levels of inducers of cyclic nucleotide synthesis,such as dopamine and nitric oxide (NO). By preventing the degradation ofcAMP and cGMP by PDE1B, thereby increasing intracellular levels of cAMPand cGMP, the Compounds of the Invention potentiate the activity ofcyclic nucleotide synthesis inducers.

The invention provides methods of treatment of any one or more of thefollowing conditions:

-   -   (i) Neurodegenerative diseases, including Parkinson's disease,        restless leg, tremors, dyskinesias, Huntington's disease,        Alzheimer's disease, and drug-induced movement disorders;    -   (ii) Mental disorders, including depression, attention deficit        disorder, attention deficit hyperactivity disorder, bipolar        illness, anxiety, sleep disorders, e.g., narcolepsy, cognitive        impairment, dementia, Tourette's syndrome, autism, fragile X        syndrome, psychostimulant withdrawal, and drug addiction;    -   (iii) Circulatory and cardiovascular disorders, including        cerebrovascular disease, stroke, congestive heart disease,        hypertension, pulmonary hypertension, and sexual dysfunction;    -   (iv) Respiratory and inflammatory disorders, including asthma,        chronic obstructive pulmonary disease, and allergic rhinitis, as        well as autoimmune and inflammatory diseases;    -   (v) Any disease or condition characterized by low levels of cAMP        and/or cGMP (or inhibition of cAMP and/or cGMP signaling        pathways) in cells expressing PDE1; and/or    -   (vi) Any disease or condition characterized by reduced dopamine        D1 receptor signaling activity,        comprising administering an effective amount of a Compound of        the Invention, e.g., a compound according to any of Formula II-A        or II-B, e.g., any of 1.1-1.84, or any of III-A, III-B, IV-A,        IV-B, V-A, V-B, VI-A, VI-B, VII-A, VII-B, VIII-A, VIII-B, IX-A,        IX-B, X-A, X-B, XI-A or XI-B, in free or pharmaceutically        acceptable salt form, to a human or animal patient in need        thereof.

In an especially preferred embodiment, the invention provides methods oftreatment or prophylaxis for narcolepsy. In this embodiment, PDE 1Inhibitors may be used as a sole therapeutic agent, but may also be usedin combination or for co-administration with other active agents. Thus,the invention further comprises a method of treating narcolepsycomprising administering simultaneously, sequentially, orcontemporaneously administering therapeutically effective amounts of

-   -   (i) a PDE 1 Inhibitor, e.g., a compound according to any of        Formula II-A or II-B, e.g., any of 1.1-1.84, or any of III-A,        III-B, IV-A, IV-B, V-A, V-B, VI-A, VI-B, VII-A, VII-B, VIII-A,        VIII-B, IX-A, IX-B, X-A, X-B, XI-A or XI-B, and    -   (ii) a compound to promote wakefulness or regulate sleep, e.g.,        selected from (a) central nervous system stimulants-amphetamines        and amphetamine like compounds, e.g., methylphenidate,        dextroamphetamine, methamphetamine, and pemoline; (b)        modafinil, (c) antidepressants, e.g., tricyclics (including        imipramine, desipramine, clomipramine, and protriptyline) and        selective serotonin reuptake inhibitors (including fluoxetine        and sertraline); and/or (d) gamma hydroxybutyrate (GHB).        in free or pharmaceutically acceptable salt form, to a human or        animal patient in need thereof.

In another embodiment, the invention further provides methods oftreatment or prophylaxis of a condition which may be alleviated by theenhancement of the progesterone signaling comprising administering aneffective amount of a Compound of the Invention, in free orpharmaceutically acceptable salt form, to a human or animal patient inneed thereof. In still another embodiment, the invention furtherprovides methods of treatment or prophylaxis of a condition which may bealleviated by the enhancement of the progesterone signaling comprisingadministering an effective amount of a Compound of the Invention, infree or pharmaceutically acceptable salt form, to a human or animalpatient in need thereof. Disease or condition that may be ameliorated byenhancement of progesterone signaling include, but are not limited to,female sexual dysfunction, secondary amenorrhea (e.g., exerciseamenorrhoea, anovulation, menopause, menopausal symptoms,hypothyroidism), pre-menstrual syndrome, premature labor, infertility,for example infertility due to repeated miscarriage, irregular menstrualcycles, abnormal uterine bleeding, osteoporosis, autoimmmune disease,multiple sclerosis, prostate enlargement, prostate cancer, andhypothyroidism. For example, by enhancing progesterone signaling, thePDE 1 inhibitors may be used to encourage egg implantation througheffects on the lining of uterus, and to help maintain pregnancy in womenwho are prone to miscarriage due to immune response to pregnancy or lowprogesterone function. The novel PDE 1 inhibitors, e.g., as describedherein, may also be useful to enhance the effectiveness of hormonereplacement therapy, e.g., administered in combination withestrogen/estradiol/estriol and/or progesterone/progestins inpostmenopausal women, and estrogen-induced endometrial hyperplasia andcarcinoma. The methods of the invention are also useful for animalbreeding, for example to induce sexual receptivity and/or estrus in anonhuman female mammal to be bred.

In this embodiment, PDE 1 Inhibitors may be used in the foregoingmethods of treatment or prophylaxis as a sole therapeutic agent, but mayalso be used in combination or for co-administration with other activeagents, for example in conjunction with hormone replacement therapy.Thus, the invention further comprises a method of treating disordersthat may be ameliorated by enhancement of progesterone signalingcomprising administering simultaneously, sequentially, orcontemporaneously administering therapeutically effective amounts of

-   -   (i) a PDE 1 Inhibitor, e.g., a compound according to any of        Formula II-A or II-B, e.g., any of 1.1-1.84, or any of III-A,        III-B, IV-A, IV-B, V-A, V-B, VI-A, VI-B, VII-A, VII-B, VIII-A,        VIII-B, IX-A, IX-B, X-A, X-B, XI-A or XI-B, and    -   (ii) a hormone, e.g., selected from estrogen and estrogen        analogues (e.g., estradiol, estriol, estradiol esters) and        progesterone and progesterone analogues (e.g., progestins)        in free or pharmaceutically acceptable salt form, to a human or        animal patient in need thereof.

The invention also provides a method for enhancing or potentiatingdopamine D1 intracellular signaling activity in a cell or tissuecomprising contacting said cell or tissue with an amount of a Compoundof the Invention, in free or salt form sufficient to inhibit PDE1Bactivity.

The invention also provides a method for treating a PDE1-related,especially PDE1B-related disorder, a dopamine D1 receptor intracellularsignaling pathway disorder, or disorders that may be alleviated by theenhancement of the progesterone signaling pathway in a patient in needthereof comprising administering to the patient an effective amount of aCompound of the Invention, in free or pharmaceutically acceptable saltform that inhibits PDE1B, wherein PDE1B activity modulatesphosphorylation of DARPP-32 and/or the GluR1 AMPA receptor.

“The Compound of the Invention” or “a PDE1 Inhibitor of the Invention”referred to herein includes optionally substituted (1- or3-oxy)-4,5,7,8-tetrahydro-(optionally 4-oxo, 4-thioxo or4-imino)-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or (1- or3-oxy)-4,5,7,8,9-pentahydro-(optionally 4-oxo, 4-thioxo or4-imino)-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine, or a Compound ofFormula II-A or II-B, e.g., any of 1.1-1.84, or any of III-A, III-B,IV-A, IV-B, V-A, V-B, VI-A, VI-B, VII-A, VII-B, VIII-A, VIII-B, IX-A,IX-B, X-A, X-B, XI-A or XI-B, in free or (pharmaceutically) acceptablesalt form.

In another aspect, the invention also provides a method for thetreatment for glaucoma or elevated intraocular pressure comprisingtopical administration of a therapeutically effective amount of aphosphodiesterase type I (PDE1) Inhibitor of the Invention, in free orpharmaceutically acceptable salt form, in an ophthalmically compatiblecarrier to the eye of a patient in need thereof. However, treatment mayalternatively include a systemic therapy. Systemic therapy includestreatment that can directly reach the bloodstream, or oral methods ofadministration, for example.

The invention further provides a pharmaceutical composition for topicalophthalmic use comprising a PDE1 inhibitor; for example an ophthalmicsolution, suspension, cream or ointment comprising a PDE1 Inhibitor ofthe Invention, in free or ophthalmologically acceptable salt form, incombination or association with an ophthalmologically acceptable diluentor carrier.

Optionally, the PDE1 Inhibitor of the Invention may be administeredsequentially or simultaneously with a second drug useful for treatmentof glaucoma or elevated intraocular pressure. Where two active agentsare administered, the therapeutically effective amount of each agent maybe below the amount needed for activity as monotherapy. Accordingly, asubthreshold amount (i.e., an amount below the level necessary forefficacy as monotherapy) may be considered therapeutically effective andalso may also be referred alternatively as an effective amount. Indeed,an advantage of administering different agents with different mechanismsof action and different side effect profiles may be to reduce the dosageand side effects of either or both agents, as well as to enhance orpotentiate their activity as monotherapy.

The invention thus provides the method of treatment of a conditionselected from glaucoma and elevated intraocular pressure comprisingadministering to a patient in need thereof an effective amount, e.g., asubthreshold amount, of an agent known to lower intraocular pressureconcomitantly, simultaneously or sequentially with an effective amount,e.g., a subthreshold amount, of a PDE1 Inhibitor of the Invention, infree or pharmaceutically acceptable salt form, such that amount of theagent known to lower intraocular pressure and the amount of the PDE1inhibitor in combination are effective to treat the condition.

In one embodiment, one or both of the agents are administered topicallyto the eye. Thus the invention provides a method of reducing the sideeffects of treatment of glaucoma or elevated intraocular pressure byadministering a reduced dose of an agent known to lower intraocularpressure concomitantly, simultaneously or sequentially with an effectiveamount of a PDE1 inhibitor. However, methods other than topicaladministration, such as systemic therapeutic administration, may also beutilized.

The optional additional agent or agents for use in combination with aPDE1 Inhibitor of the Invention may, for example, be selected from theexisting drugs comprise typically of instillation of a prostaglandin,pilocarpine, epinephrine, or topical beta-blocker treatment, e.g. withtimolol, as well as systemically administered inhibitors of carbonicanhydrase, e.g. acetazolamide. Cholinesterase inhibitors such asphysostigmine and echothiopate may also be employed and have an effectsimilar to that of pilocarpine. Drugs currently used to treat glaucomathus include, e.g.,

-   -   1. Prostaglandin analogs such as latanoprost (Xalatan),        bimatoprost (Lumigan) and travoprost (Travatan), which increase        uveoscleral outflow of aqueous humor. Bimatoprost also increases        trabecular outflow.    -   2. Topical beta-adrenergic receptor antagonists such as timolol,        levobunolol (Betagan), and betaxolol, which decrease aqueous        humor production by the ciliary body.    -   3. Alpha₂-adrenergic agonists such as brimonidine (Alphagan),        which work by a dual mechanism, decreasing aqueous production        and increasing uveo-scleral outflow.    -   4. Less-selective sympathomimetics like epinephrine and        dipivefrin (Propine) increase outflow of aqueous humor through        trabecular meshwork and possibly through uveoscleral outflow        pathway, probably by a beta₂-agonist action.    -   5. Miotic agents (parasympathomimetics) like pilocarpine work by        contraction of the ciliary muscle, tightening the trabecular        meshwork and allowing increased outflow of the aqueous humour.    -   6. Carbonic anhydrase inhibitors like dorzolamide (Trusopt),        brinzolamide (Azopt), acetazolamide (Diamox) lower secretion of        aqueous humor by inhibiting carbonic anhydrase in the ciliary        body.    -   7. Physostigmine is also used to treat glaucoma and delayed        gastric emptying.

For example, the invention provides pharmaceutical compositionscomprising a PDE1 Inhibitor of the Invention and an agent selected from(i) the prostanoids, unoprostone, latanoprost, travoprost, orbimatoprost; (ii) an alpha adrenergic agonist such as brimonidine,apraclonidine, or dipivefrin and (iii) a muscarinic agonist, such aspilocarpine. For example, the invention provides ophthalmic formulationscomprising a PDE-1 Inhibitor of the Invention together with bimatoprost,abrimonidine, brimonidine, timolol, or combinations thereof, in free orophthamalogically acceptable salt form, in combination or associationwith an ophthamologically acceptable diluent or carrier. In addition toselecting a combination, however, a person of ordinary skill in the artcan select an appropriate selective receptor subtype agonist orantagonist. For example, for alpha adrenergic agonist, one can select anagonist selective for an alpha 1 adrenergic receptor, or an agonistselective for an alpha₂ adrenergic receptor such as brimonidine, forexample. For a beta-adrenergic receptor antagonist, one can select anantagonist selective for either β₁, or β₂, or β₃, depending on theappropriate therapeutic application. One can also select a muscarinicagonist selective for a particular receptor subtype such as M₁-M₅.

The PDE 1 Inhibitor of the Invention may be administered in the form ofan ophthalmic composition, which includes an ophthalmic solution, creamor ointment. The ophthalmic composition may additionally include anintraocular-pressure lowering agent.

In yet another example, the PDE-1 Inhibitors of the Invention disclosedmay be combined with a subthreshold amount of an intraocularpressure-lowering agent which may be a bimatoprost ophthalmic solution,a brimonidine tartrate ophthalmic solution, or brimonidinetartrate/timolol maleate ophthalmic solution.

In addition to the above-mentioned methods, it has also beensurprisingly discovered that PDE1 Inhibitors of the Invention are usefulto treat psychosis, for example, any conditions characterized bypsychotic symptoms such as hallucinations, paranoid or bizarredelusions, or disorganized speech and thinking, e.g., schizophrenia,schizoaffective disorder, schizophreniform disorder, psychotic disorder,delusional disorder, and mania, such as in acute manic episodes andbipolar disorder. Without intending to be bound by any theory, it isbelieved that typical and atypical antipsychotic drugs such as clozapineprimarily have their antagonistic activity at the dopamine D2 receptor.PDE1 inhibitors, however, primarily act to enhance signaling at thedopamine D1 receptor. By enhancing D1 receptor signaling, PDE1inhibitors can increase NMDA receptor function in various brain regions,for example in nucleus accumbens neurons and in the prefrontal cortex.This enhancement of function may be seen for example in NMDA receptorscontaining the NR2B subunit, and may occur e.g., via activation of theSrc and protein kinase A family of kinases.

Therefore, the invention provides a new method for the treatment ofpsychosis, e.g., schizophrenia, schizoaffective disorder,schizophreniform disorder, psychotic disorder, delusional disorder, andmania, such as in acute manic episodes and bipolar disorder, comprisingadministering a therapeutically effective amount of aphosphodiesterase-1 (PDE1) Inhibitor of the Invention, in free orpharmaceutically acceptable salt form, to a patient in need thereof.

PDE 1 Inhibitors of the Invention may be used in the foregoing methodsof treatment prophylaxis as a sole therapeutic agent, but may also beused in combination or for co-administration with other active agents.Thus, the invention further comprises a method of treating psychosis,e.g., schizophrenia, schizoaffective disorder, schizophreniformdisorder, psychotic disorder, delusional disorder, or mania, comprisingadministering simultaneously, sequentially, or contemporaneouslyadministering therapeutically effective amounts of:

-   -   (i) a PDE 1 Inhibitor of the Invention, in free or        pharmaceutically acceptable salt form; and    -   (ii) an antipsychotic, e.g.,        -   Typical antipsychotics, e.g.,            -   Butyrophenones, e.g. Haloperidol (Haldol, Serenace),                Droperidol (Droleptan);            -   Phenothiazines, e.g., Chlorpromazine (Thorazine,                Largactil), Fluphenazine (Prolixin), Perphenazine                (Trilafon), Prochlorperazine (Compazine), Thioridazine                (Mellaril, Melleril), Trifluoperazine (Stelazine),                Mesoridazine, Periciazine, Promazine, Triflupromazine                (Vesprin), Levomepromazine (Nozinan), Promethazine                (Phenergan), Pimozide (Orap);            -   Thioxanthenes, e.g., Chlorprothixene, Flupenthixol                (Depixol, Fluanxol), Thiothixene (Navane),                Zuclopenthixol (Clopixol, Acuphase);        -   Atypical antipsychotics, e.g.,            -   Clozapine (Clozaril), Olanzapine (Zyprexa), Risperidone                (Risperdal), Quetiapine (Seroquel), Ziprasidone                (Geodon), Amisulpride (Solian), Paliperidone (Invega),                Aripiprazole (Abilify), Bifeprunox; norclozapine,    -   in free or pharmaceutically acceptable salt form, to a patient        in need thereof.

In a particular embodiment, the Compounds of the Invention areparticularly useful for the treatment or prophylaxis of schizophrenia.

Compounds of the Invention, in free or pharmaceutically acceptable saltform, are particularly useful for the treatment of Parkinson's disease,schizophrenia, narcolepsy, glaucoma and female sexual dysfunction.

In still another aspect, the invention provides a method of lengtheningor enhancing growth of the eyelashes by administering an effectiveamount of a prostaglandin analogue, e.g., bimatoprost, concomitantly,simultaneously or sequentially with an effective amount of a PDE1Inhibitor of the Invention, in free or pharmaceutically acceptable saltform, to the eye of a patient in need thereof.

In yet another aspect, the invention provides a method for the treatmentor prophylaxis of traumatic brain injury comprising administering atherapeutically effective amount of a Compound of the Invention, in freeor pharmaceutically acceptable salt form, to a patient in need thereof.Traumatic brain injury (TBI) encompasses primary injury as well assecondary injury, including both focal and diffuse brain injuries.Secondary injuries are multiple, parallel, interacting andinterdependent cascades of biological reactions arising from discretesubcellular processes (e.g., toxicity due to reactive oxygen species,overstimulation of glutamate receptors, excessive influx of calcium andinflammatory upregulation) which are caused or exacerbated by theinflammatory response and progress after the initial (primary) injury.Abnormal calcium homeostasis is believed to be a critical component ofthe progression of secondary injury in both grey and white matter. For areview of TBI, see Park et al., CMAJ (2008) 178(9):1163-1170, thecontents of which are incorporated herein in their entirety. Studieshave shown that the cAMP-PKA signaling cascade is downregulated afterTBI and treatment of PDE IV inhibitors such as rolipram to raise orrestore cAMP level improves histopathological outcome and decreasesinflammation after TBI. As Compounds of the present invention is a PDE1inhibitor, it is believed that these compounds are also useful for thetreatment of TBI, e.g., by restoring cAMP level and/or calciumhomeostasis after traumatic brain injury.

The present invention also provides

-   -   (i) a Compound of the Invention, in free or pharmaceutically        acceptable salt form, for use as a pharmaceutical, for example        for use in any method or in the treatment of any disease or        condition as hereinbefore set forth,    -   (ii) the use of a Compound of the Invention, in free or        pharmaceutically acceptable salt form, in the manufacture of a        medicament for treating any disease or condition as hereinbefore        set forth,    -   (iii) a pharmaceutical composition comprising a Compound of the        Invention, in free or pharmaceutically acceptable salt form, in        combination or association with a pharmaceutically acceptable        diluent or carrier, and    -   (iv) a pharmaceutical composition comprising a Compound of the        Invention, in free or pharmaceutically acceptable salt form, in        combination or association with a pharmaceutically acceptable        diluent or carrier for use in the treatment of any disease or        condition as hereinbefore set forth.

Therefore, the invention provides use of a Compound of the Invention, infree or pharmaceutically acceptable salt or prodrug form, or a Compoundof the Invention in a pharmaceutical composition form, (for themanufacture of a medicament) for the treatment or prophylactic treatmentof the following diseases: Parkinson's disease, restless leg, tremors,dyskinesias, Huntington's disease, Alzheimer's disease, and drug-inducedmovement disorders; depression, attention deficit disorder, attentiondeficit hyperactivity disorder, bipolar illness, anxiety, sleepdisorder, narcolepsy, cognitive impairment, dementia, Tourette'ssyndrome, autism, fragile X syndrome, psychostimulant withdrawal, and/ordrug addiction; cerebrovascular disease, stroke, congestive heartdisease, hypertension, pulmonary hypertension, and/or sexualdysfunction; asthma, chronic obstructive pulmonary disease, and/orallergic rhinitis, as well as autoimmune and inflammatory diseases;and/or female sexual dysfunction, exercise amenorrhoea, anovulation,menopause, menopausal symptoms, hypothyroidism, pre-menstrual syndrome,premature labor, infertility, irregular menstrual cycles, abnormaluterine bleeding, osteoporosis, multiple sclerosis, prostateenlargement, prostate cancer, hypothyroidism, estrogen-inducedendometrial hyperplasia or carcinoma; and/or any disease or conditioncharacterized by low levels of cAMP and/or cGMP (or inhibition of cAMPand/or cGMP signaling pathways) in cells expressing PDE1, and/or byreduced dopamine D1 receptor signaling activity; and/or any disease orcondition that may be ameliorated by the enhancement of progesteronesignaling.

The invention also provides use of a Compound of the Invention, in freeor pharmaceutically acceptable salt form, (for the manufacture of amedicament) for the treatment or prophylactic treatment of:

-   -   a) glaucoma or elevated intraocular pressure,    -   b) psychosis, for example, any conditions characterized by        psychotic symptoms such as hallucinations, paranoid or bizarre        delusions, or disorganized speech and thinking, e.g.,        schizophrenia, schizoaffective disorder, schizophreniform        disorder, psychotic disorder, delusional disorder, and mania,        such as in acute manic episodes and bipolar disorder,    -   c) traumatic brain injury.

The words “treatment” and “treating” are to be understood accordingly asembracing prophylaxis and treatment or amelioration of symptoms ofdisease as well as treatment of the cause of the disease.

For methods of treatment, the word “effective amount” is intended toencompass a therapeutically effective amount to treat a specific diseaseor disorder.

The term “pulmonary hypertension” is intended to encompass pulmonaryarterial hypertension.

The term “patient” include human or non-human (i.e., animal) patient. Inparticular embodiment, the invention encompasses both human andnonhuman. In another embodiment, the invention encompasses nonhuman. Inother embodiment, the term encompasses human.

The term “comprising” as used in this disclosure is intended to beopen-ended and does not exclude additional, unrecited elements or methodsteps.

Compounds of the Invention are in particular useful for the treatment ofParkinson's disease, narcolepsy and female sexual dysfunction.

Compounds of the Invention, in free or pharmaceutically acceptable saltform may be used as a sole therapeutic agent, but may also be used incombination or for co-administration with other active agents. Forexample, as Compounds of the Invention potentiate the activity of D1agonists, such as dopamine, they may be simultaneously, sequentially, orcontemporaneously administered with conventional dopaminergicmedications, such as levodopa and levodopa adjuncts (carbidopa, COMTinhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergics,e.g., in the treatment of a patient having Parkinson's disease. Inaddition, the novel PDE 1 inhibitors, e.g., as described herein, mayalso be administered in combination with estrogen/estradiol/estrioland/or progesterone/progestins to enhance the effectiveness of hormonereplacement therapy or treatment of estrogen-induced endometrialhyperplasia or carcinoma.

Dosages employed in practicing the present invention will of course varydepending, e.g. on the particular disease or condition to be treated,the particular Compound of the Invention used, the mode ofadministration, and the therapy desired. Compounds of the Invention maybe administered by any suitable route, including orally, parenterally,transdermally, or by inhalation, but are preferably administered orally.In general, satisfactory results, e.g. for the treatment of diseases ashereinbefore set forth are indicated to be obtained on oraladministration at dosages of the order from about 0.01 to 2.0 mg/kg. Inlarger mammals, for example humans, an indicated daily dosage for oraladministration will accordingly be in the range of from about 0.75 to150 mg, conveniently administered once, or in divided doses 2 to 4times, daily or in sustained release form. Unit dosage forms for oraladministration thus for example may comprise from about 0.2 to 75 or 150mg, e.g. from about 0.2 or 2.0 to 50, 75 or 100 mg of a Compound of theInvention, together with a pharmaceutically acceptable diluent orcarrier therefor.

Pharmaceutical compositions comprising Compounds of the Invention may beprepared using conventional diluents or excipients and techniques knownin the galenic art. Thus oral dosage forms may include tablets,capsules, solutions, suspensions and the like.

EXAMPLES

The synthetic methods for various Compounds of the Present Invention areillustrated below. Other compounds of the Invention and their salts maybe made using the methods as similarly described below and/or by methodssimilar to those generally described in the detailed description and bymethods known in the chemical art.

Example 1(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenoxy)-2-(4-methoxy-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one

Step 1:2-((1R,2R)-2-hydroxycyclopentylamino)-3-methylpyrimidin-4(3H)-one

3-Methyluracil (12.6 mg, 0.1 mmol) is dissolved in 0.5 mL of DMF, andthen BOP (71 mg, 0.16 mmol) is added. The mixture is stirred at roomtemperature for two minutes, and then(1R,2R)-(−)-2-hydroxycyclopentylamine hydrochloride salt (22 mg, 0.16mmol) is added, followed by DBU (51 uL, 3.4 mmol). The reaction mixtureis stirred at room temperature overnight, and then purified by asemi-preparative HPLC to give pure product (16 mg, yield 76%). MS (ESI)m/z 210.1 [M+H]⁺.

Step 2:(3aS,8aR)-7-Methyl-1,2,3,3a,7,8a-hexahydro-3b,7,8-triaza-cyclopenta[a]inden-6-one

To a solution of2-((1R,2R)-2-hydroxycyclopentylamino)-3-methylpyrimidin-4(3H)-one (130mg, 0.62 mmol) in anhydrous THF (2 mL) is added triphenylphosphine (163mg, 0.62 mmol). After five minutes, diethyl azodicarboxylate (DEAD, 0.45mL, 0.93 mmol) in toluene is added dropwise. The mixture is stirred atroom temperature for 2 hours. After solvent is removed under reducedpressure, the residue is treated with 0.02 N HCl (40 mL). Theprecipitate is filtered off, and the filtrate is washed with CH₂Cl₂. Theaqueous phase is evaporated to dryness under high vacuum to give productas solids (108 mg, yield 92%), which is used in the next step withoutfurther purification. MS (ESI) m/z 192.1 [M+H]⁺.

Step 3:(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one

Sodium hydride (95%, 112 mg, 4.44 mmol) is suspended in 3 mL ofanhydrous THF, and then a mixture of(3aS,8aR)-7-Methyl-1,2,3,3a,7,8a-hexahydro-3b,7,8-triaza-cyclopenta[a]inden-6-one(283 mg, 1.48 mmol) and p-toluenesulfonylmethyl isocyanide (97%, 347 mg,1.77 mmol) in 5 mL of anhydrous THF is added dropwise. The mixture isstirred at room temperature for an hour, and then quenched with water.The mixture is extracted with CH₂Cl₂ five times (5×10 mL). The combinedorganic phase is washed with brine, and then dried with anhydrousNa₂SO₄. After filtration, the filtrate is evaporated to dryness underreduced pressure to give crude product (320 mg, yield 94%) as brownsolids, which is used in the next step without further purification. MS(ESI) m/z 231.1 [M+H]⁺.

Step 4:(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-methoxy-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one

A suspension of(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one(500 mg, 2.2 mmol), 1-(chloromethyl)-4-methoxybenzene (0.38 mL, 2.8mmol) and cesium carbonate (1.3 mg, 1.8 mmol) in anhydrous DMF isstirred at room temperature for 3 h. The mixture is diluted withsaturated NaHCO₃ aqueous solution, and then extracted with CH₂Cl₂/MeOH(10:1) three times. The combined organic phase is dried over anhydroussodium sulfate, and then filtered through a layer of celite. Thefiltrate is concentrated, and then purified by silica-gel columnchromatography to give product as beige solids. MS (ESI) m/z 351.2[M+11]⁺.

Step 5:(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-2-(4-methoxy-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one

1.0M LiHMDS in THF (4.2 mL, 4.2 mmol) is added dropwise to a solution of(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-methoxy-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one(500 mg, 1.4 mmol) and hexachloroethane (1.69 g, 7.13 mmol) at roomtemperature under argon. After 30 min, the mixture is quenched withsaturated ammonium chloride aqueous solution at 0° C., and then basifiedwith saturated sodium bicarbonate aqueous solution, followed byextractions with methylene chloride. The collected organic phase iswashed with brine, dried over anhydrous sodium sulfate, and thenevaporated to dryness under reduced pressure. The obtained crude productis purified by silica gel flash chromatography to give 165 mg of pureproduct as off white solid (yield: 30%). MS (ESI) m/z 385.2 [M+H]⁺.

Step 6:(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenoxy)-2-(4-methoxy-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one

(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-2-(4-methoxy-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one(22 mg, 0.057 mmol), phenol (27 mg, 0.28 mmol) and K₂CO₃ (24 mg, 0.17mmol) are placed in a microwave vial, and then dioxane (0.3 mL) isadded. The vial is sealed and heated in a Biotage microwave instrumentat 160° C. for 6 h. The reaction mixture is then purified with asemi-preparative HPLC to give pure product as off-white solid. MS (ESI)m/z 443.2 [M+H]⁺.

Example 2

Measurement of PDE1B Inhibition In Vitro Using IMAP PhosphodiesteraseAssay Kit

Phosphodiesterase 1B (PDE1B) is a calcium/calmodulin dependentphosphodiesterase enzyme that converts cyclic guanosine monophosphate(cGMP) to 5′-guanosine monophosphate (5′-GMP). PDE1B can also convert amodified cGMP substrate, such as the fluorescent moleculecGMP-fluorescein, to the corresponding GMP-fluorescein. The generationof GMP-fluorescein from cGMP-fluorescein can be quantitated, using, forexample, the IMAP (Molecular Devices, Sunnyvale, Calif.)immobilized-metal affinity particle reagent.

Briefly, the IMAP reagent binds with high affinity to the free5′-phosphate that is found in GMP-fluorescein and not incGMP-fluorescein. The resulting GMP-fluorescein—IMAP complex is largerelative to cGMP-fluorescein. Small fluorophores that are bound up in alarge, slowly tumbling, complex can be distinguished from unboundfluorophores, because the photons emitted as they fluoresce retain thesame polarity as the photons used to excite the fluorescence.

In the phosphodiesterase assay, cGMP-fluorescein, which cannot be boundto IMAP, and therefore retains little fluorescence polarization, isconverted to GMP-fluorescein, which, when bound to IMAP, yields a largeincrease in fluorescence polarization (Δmp) Inhibition ofphosphodiesterase, therefore, is detected as a decrease in Δmp.

Enzyme Assay

-   Materials: All chemicals are available from Sigma-Aldrich (St.    Louis, Mo.) except for IMAP reagents (reaction buffer, binding    buffer, FL-GMP and IMAP beads), which are available from Molecular    Devices (Sunnyvale, Calif.).-   Assay: 3′,5′-cyclic-nucleotide-specific bovine brain    phosphodiesterase (Sigma, St. Louis, Mo.) is reconstituted with 50%    glycerol to 2.5 U/ml. One unit of enzyme will hydrolyze 1.0 μmole of    3′,5′-cAMP to 5′-AMP per min at pH 7.5 at 30° C. One part enzyme is    added to 1999 parts reaction buffer (30 μM CaCl₂, 10 U/ml of    calmodulin (Sigma P2277), 10 mM Tris-HCl pH 7.2, 10 mM MgCl₂, 0.1%    BSA, 0.05% NaN₃) to yield a final concentration of 1.25 mU/ml. 99 μl    of diluted enzyme solution is added into each well in a flat bottom    96-well polystyrene plate to which 1 μl of test compound dissolved    in 100% DMSO is added. The compounds are mixed and pre-incubated    with the enzyme for 10 min at room temperature.

The FL-GMP conversion reaction is initiated by combining 4 parts enzymeand inhibitor mix with 1 part substrate solution (0.225 μM) in a384-well microtiter plate. The reaction is incubated in dark at roomtemperature for 15 min. The reaction is halted by addition of 60 μl ofbinding reagent (1:400 dilution of IMAP beads in binding buffersupplemented with 1:1800 dilution of antifoam) to each well of the384-well plate. The plate is incubated at room temperature for 1 hour toallow IMAP binding to proceed to completion, and then placed in anEnvision multimode microplate reader (PerkinElmer, Shelton, Conn.) tomeasure the fluorescence polarization (Δmp).

A decrease in GMP concentration, measured as decreased Δmp, isindicative of inhibition of PDE activity. IC₅₀ values are determined bymeasuring enzyme activity in the presence of 8 to 16 concentrations ofcompound ranging from 0.0037 nM to 80,000 nM and then plotting drugconcentration versus ΔmP, which allows IC₅₀ values to be estimated usingnonlinear regression software (XLFit; IDBS, Cambridge, Mass.). Theexemplified compound of the invention has an IC₅₀ value of 15 nM,against PDE1A.

Example 3

PDE1 Inhibitor Effect on Sexual Response in Female Rats

The effect of PDE1 inhibitors on Lordosis Response in female rats may bemeasured as described in Mani, et al., Science (2000) 287: 1053.Ovariectomized and cannulated wild-type rats are primed with 2 μgestrogen followed 24 hours later by intracerebroventricular (icv)injection of progesterone (2 μg), PDE1 inhibitors of the presentinvention (0.1 mg, 1.0 mg or 2.5 mg) or sesame oil vehicle (control).The rats may be tested for lordosis response in the presence of malerats. Lordosis response is quantified by the lordosis quotient(LQ=number of lordosis/10 mounts×100).

What is claimed is:
 1. A Compound of Formula II-A or II-B

wherein (i) Q is C(═O), (ii) L is —O—; (iii) R₁ is H or C₁₋₄ alkyl; R₂is H and R₃ and R₄ together form a di-, tri- or tetramethylene bridge;(iv) R₅ is c) attached to the nitrogen on the pyrrolo portion of FormulaII-A or II-B and is a moiety of Formula A

wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁ and R₁₂are independently H or halogen, and R₁₀ is halogen, C₁₋₆alkyl,C₁₋₆alkoxy, C₃₋₇cycloalkyl, heteroC₃₋₇cycloalkyl, C₁₋₆haloalkyl, aryl,heteroaryl, arylcarbonyl, C₁₋₆alkylsulfonyl, heteroarylcarbonyl, orC₁₋₆alkoxycarbonyl; wherein the aryl, heteroaryl, cycloalkyl orheterocycloalkyl is independently, optionally substituted with one ormore C₁₋₆alkyl, halogen, haloC₁₋₆alkyl, hydroxy, C₁₋₆-carboxy, —SH or anadditional aryl, heteroaryl or C₃₋₈cycloalkyl, provided that when X, Y,or Z is nitrogen, R₈, R₉, or R₁₀, respectively, is not present; (v) R₆is C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl, heteroaryl, or arylC₁₋₆alkyl,wherein the aryl or heteroaryl is optionally substituted with one ormore group selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy andC₃₋₈cycloalkyl; (vi) R₇ is H, C₁₋₆alkyl, (vii) n=0; in free or saltform.
 2. A compound selected from any one of the following: F) aCompound of Formula VIII-A or VIII-B:

wherein (i) Q is C(═O); (ii) L is —O—; (iii) R₁ is H or C₁₋₄ alkyl; (iv)R₂ is H and R₃ and R₄ together form a di- or tri- or tetramethylenebridge; (v) R₅ is attached to the nitrogen on the pyrrolo portion ofFormula VIII-A or VIII-B and is a moiety of Formula A

wherein X, Y and Z are, C; and R₈, R₉, R₁₁ and R₁₂ are H; and R₁₀ is,heteroC₃₋₇cycloalkyl, heteroaryl, wherein the heteroaryl, orheterocycloalkyl is independently, optionally substituted with one ormore C₁₋₆alkyl (e.g., (vi) R₆ is C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl,heteroaryl, or arylC₁₋₆alkyl, wherein the aryl or heteroaryl isoptionally substituted with one or more group selected from halo,hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl; (vii) R₇ is H; (viii)n=0 or 1; and (ix) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,independently, H or C₁₋₆alkyl, aryl, heteroaryl, (optionallyhetero)arylC₁₋₆alkoxy, (optionally hetero)arylC₁₋₆alkyl or R₁₄ can forma bridge with R₂ or R₄; in free or salt form; G) a Compound of FormulaIX-A or IX-B:

wherein (i) Q is C(═O); (ii) L is —O—; (iii) R₁ is H or C₁₋₆ alkyl; (iv)R₂ is H and R₃ and R₄ together form a di-, tri- or tetramethylenebridge; (v) R₅ is attached to the nitrogen on the pyrrolo portion ofFormula IX-A or IX-B and is a moiety of Formula A

wherein X, Y and Z are C; and R₈, R₉, R₁₁ and R₁₂ are H; and R₁₀ isselected from the following: pyrrolidinyl, piperidinyl, pyridyl,thiadiazolyl, diazolyl, triazolyl, tetrazolyl, wherein R₁₀ is optionallysubstituted with one or more C₁₋₆alkyl, halogen, (vi) R₆ is C₁₋₆ alkyl,C₃₋₇cycloalkyl, aryl, heteroaryl, or arylC₁₋₆alkyl, wherein the aryl orheteroaryl is optionally substituted with one or more group selectedfrom halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl; (vii) R₇is H; and (viii) n=0 in free or salt form; H) a Compound of Formula X-Aor X-B:

wherein (i) Q is C(═O); (ii) L is —O—; (iii) R₁ is H or C₁₋₄ alkyl; (iv)R₂ is H and R₃ and R₄ together form a di-, tri- or tetramethylenebridge; (v) R₅ is attached to the nitrogen on the pyrrolo portion ofFormula X-A or X-B and is a moiety of Formula A

wherein X, Y and Z are C; and R₈, R₉, R₁₁ and R₁₂ are H; and R₁₀ ispyrid-2-yl, 1,2,4-triazolyl, 6-fluoropyrid-2-yl or1-methylpyrrolidin-2-yl; (vi) R₆ is C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl,heteroaryl, or arylC₁₋₆alkyl, wherein the aryl or heteroaryl isoptionally substituted with one or more group selected from halo,hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl; (vii) R₇ is H; (viii)n=0 in free or salt form; I) a Compound of Formula XI-A or XI-B

wherein (i) Q is C(═O); (ii) L is —O—; (iii) R₁ is H or C₁₋₆ alkyl; (iv)R₂ is H and R₃ and R₄ together form a di-, tri- or tetramethylenebridge; (v) R₅ is attached to the nitrogen on the pyrrolo portion ofFormula XI-A or XI-B and is a moiety of Formula A

wherein X, Y and Z are C; and R₈, R₉, R₁₁ and R₁₂ are H; and R₁₀ isC₁₋₆alkoxy; (vi) R₆ is (vii) R₇ is H; (viii) n=0, in free or salt form.3. The compound according to claim 1, wherein said compound is:

in free or salt form.
 4. A pharmaceutical composition comprising acompound according to claim 1, in free or pharmaceutically acceptablesalt form, in admixture with a pharmaceutically acceptable diluent orcarrier.
 5. The pharmaceutical composition according to claim 4, whereinthe salt and the diluents or carrier are ophthalmically acceptable.